Derivatives of (AZA) naphthalensultam, their preparation and compositions containing them

ABSTRACT

This invention relates to a compound of the formula: ##STR1## in which R 1  represents 
     a 1,2,3,6-tetrahydro-1-pyridyl radical substituted in the 4-position. 
     a 1-piperazinyl radical substituted in the 4-position. 
     a piperidino radical substituted in the 4-position 
     either: 
     R 2  and R 3 , which are identical, represent a hydrogen or halogen atom and R 4  represents a hydrogen atom or 
     R 2  and R 4  represent a hydrogen atom and R 3  represents a halogen atom or an acetylamino radical or 
     R 2  and R 3  represent a hydrogen atom and R 4  represents a halogen atom and R 5  represents a --CH═ group. 
     or R 2 , R 3  and R 4  represent a hydrogen atom and R 5  represents a nitrogen atom. 
     R 6  represents an alkylene chain containing 2 to 4 carbon atoms or a propylene chain substituted in the 1- or 3-position by an alkyl radical or in the 2-position by an alkyl, alkoxy, hydroxy, dialkylamino, piperidino, morpholino or thiomorpholino radical, and their salts, are useful in therapy for their ability to block serotonin receptors.

This is division of co-pending application Ser. No. 375,934 filed July6, 1989.

DESCRIPTION OF THE INVENTION

The present invention provides, as new compounds, the(aza)naphthalenesultam derivatives of formula: ##STR2## in which R₁represents

a 1,2,3,6-tetrahydro-1-pyridyl radical substituted in the 4-position by(a) a phenyl radical, (b) a phenyl radical substituted by a halogen atomor an alkyl, hydroxy or alkoxy radical, (c) a 3-indolyl radical, (d) a3-indolyl radical substituted on the nitrogen atom by an alkyl oralkylcarbonyl radical and/or in the 5-position by a chlorine or fluorineatom or (e) a 3-(5-hydroxyindolyl) radical,

a 1-piperazinyl radical substituted in the 4-position by (a) a phenylradical, (b) a phenyl radical substituted by an alkoxy, alkyl, hydroxy,nitro or amino radical or a halogen atom, (c) a 1,2-benzisothiazol-3-ylradical, (d) a 1,2-benzisoxazol-3-yl radical or (e) a 2-pyridyl radical,

a piperidino radical substituted in the 4-position by (a) a phenylradical, (b) a phenyl radical substituted by a halogen atom or ahydroxy, alkyl or alkoxy radical, (c) two phenyl radicals, (d) abis(4-fluorophenyl)methylene radical, (e) a 4-fluorobenzoyl radical, (f)a 2-oxo-1-benzimidazolinyl radical, (g) a 2-oxo-1-benzimidazolinylradical substituted in the 3-position by an alkylcarbonyl or benzoylradical, (h) a hydroxy radical and a phenyl radical optionallysubstituted with an alkyl, alkoxy or hydroxy radical or a halogen atom,(i) a 3-indolyl radical, (j) a 3-indolyl radical substituted on thenitrogen atom by an alkyl or alkylcarbonyl radical and/or in the5-position by a chlorine or fluorine atom or (k) a 3-(5-hydroxyindolyl)radical,

either:

R₂ and R₃, which are identical, represent a hydrogen or halogen atom andR₄ represents a hydrogen atom or

R₂ and R₄ represent a hydrogen atom and R₃ represents a halogen atom oran acetylamino radical or

R₂ and R₃ represent a hydrogen atom and R₄ represents a halogen atom

and R₅ represents a --CH═ group,

or R₂, R₃ and R₄ represent a hydrogen atom and R₅ represents a nitrogenatom,

R₆ represents an alkylene chain containing 2 to 4 carbon atoms or apropylene chain substituted in the 1- or 3-position by an alkyl radicalor in the 2-position by an alkyl, alkoxy, hydroxy, dialkylamino,piperidino, morpholino or thiomorpholino radical,

with the reservation that when R₆ represents a propylene radicalsubstituted in the 2-position with a dialkylamino, piperidino,morpholino or thiomorpholino radical, R₁ cannot be a radical containinga hydroxy radical.

In the preceding definitions, and those mentioned below, the alkyl andalkoxy radicals and the alkyl and alkoxy portions each contain 1 to 4carbon atoms in a straight or branched chain and the halogen atoms arepreferably chlorine or bromine atoms.

The invention also provides the salts of compounds of formula (I) withinorganic or organic acids.

The compounds of formula (I) in which R₁, R₂, R₃, R₄ and R₅ have themeanings mentioned above, with the reservation that R₁ cannot be a4-aminophenyl-1-piperazinyl radical, and/or R₆ cannot be a propyleneradical substituted in the 2-position by a dialkylamino, piperidino,morpholino or thiomorpholino radical, may be prepared by the action of ahalogenated derivative of formula: ##STR3## in which R₂, R₃, R₄, R₅ andR₆ have the same meanings as above and Hal represents a halogen atom ona compound of formula:

    HR.sub.1                                                   (III)

in which R₁ has the same meanings as in formula (I) with the reservationthat R₁ cannot be a 4-aminophenyl-1-piperazinyl radical or a salt ofsuch a compound with an acid.

This reaction generally takes place in the presence of a base such as analkali-metal carbonate or of an organic base such as1,8-diazabicyclo[5,4,0]-7-undecene, 1,5-diazabicyclo[4,3,0]-5-nonene ortriethylamine, optionally in the presence of sodium iodide, in anorganic solvent such as benzene, toluene, dimethylformamide,acetonitrile, tetrahydrofuran or acetone, at a temperature of between20° C. and the boiling point of the solvent.

The halogenated derivatives of formula (II) for which

R₅ represents a --CH═, and

either R₂, R₃ and R₄ represent a hydrogen atom,

or R₂ and R₃ represent a halogen atom and R₄ represents a hydrogen atom,

or R₂ and R₄ represent a hydrogen atom and R₃ represents a halogen atom,

or R₂ and R₃ represent a hydrogen atom and R₄ represents a halogen atom,

or even R₅ represents a nitrogen atom and R₂, R₃ and R₄ represent ahydrogen atom,

and R₆ represents an alkylene (2-4 C) radical or a propylene radicalsubstituted in the 2-position by a hydroxy, alkyl or alkoxy radical

can be prepared by the action of a compound of formula: ##STR4## inwhich R₂, R₃, R₄ and R₅ have the same meanings as above, on a compoundof formula:

    X--R.sub.6 --Hal                                           (V)

in which R₆ represents an alkylene (2-4 C) radical or a propyleneradical substituted in the 2-position by a hydroxy, alkyl or alkoxyradical, and Hal and X represent a halogen atom.

This reaction preferably takes place in the presence of a base such asan alkali-metal hydride, an alkali-metal hydroxide or an alkali-metalcarbonate, in an inert solvent such as dimethylformamide ortetrahydrofuran, at a temperature of between 20° C. and the boilingpoint of the solvent.

The compounds of formula (IV) for which R₅ represents a ═CH-- group, R₂and R₄ represent a hydrogen atom and R₃ represents a halogen atom, maybe prepared by application or adaptation of the methods described by A.MUSTAFA et al., Arch. Pharm., 298, 741 (1965).

The compounds of formula (IV) for which R₅ represents a ═CH-- group, R₂and R₃ represent a hydrogen atom and R₄ represents a halogen atom, maybe prepared by cyclization of a compound of formula: ##STR5## in whichR₄ has the same meanings as above.

This cyclization is carried out, for example, by means of phosphorusoxychloride, at the boiling point of the reaction medium, by adaptationof the method described by F. DANNERTH et al., J. Am. Chem. Soc., 29,1319 (1907).

The compounds of formula (VI) may obtained by application or adaptationof the method described by P. FRIEDLANDER et al., Chem. Ber., 55B, 45(1922).

The compounds of formula (IV) for which R₅ represents a ═CH-- group, R₂and R₃ represent a halogen atom and R₄ represents a hydrogen atom may beprepared by application or adaptation of the method described by Th.ZINCKE et al., Liebigs Ann. Chem., 411, 195 (1916).

The compound of formula (IV) for which R₅ represents a nitrogen atom maybe obtained by cyclization of 4-bromo-5-isoquinolylsulphonamide.

This cyclization is preferably carried out by means of a base such as analkali-metal hydride, in an inert organic solvent such asdimethylformamide or tetrahydrofuran, at a temperature of between 20° C.and the boiling point of the solvent.

4-Bromo-5-isoquinolylsulphonamide may be prepared by the action ofammonia on 4-bromo-5-isoquinolylsulphonyl chloride, preferably intetrahydrofuran, at a temperature varying from -50° C. to 20° C.

4-Bromo-5-isoquinolylsulphonyl chloride may be prepared by the action ofsodium nitrite on 5-amino-4-bromoisoquinoline in the presence ofhydrochloric acid at a temperature of about 0° C., then of sulphurdioxide in acetic acid in the presence of cuprous chloride at atemperature of about 20° C.

5-Amino-4-bromoisoquinoline may be obtained by reduction of4-bromo-5-nitroisoquinoline. This reduction is preferably carried out bymeans of stannous chloride and hydrochloric acid at the boiling point ofthe reaction mixture.

4-Bromo-5-nitroisoquinoline may be prepared by application of the methoddescribed by M. D. Nair et al., Indian J. Chem. Soc., 5, 224 (1967).

The derivatives of formula (V) for which R₆ represents an alkylene (2-4C) radical or a propylene radical substituted in the 2-position by ahydroxy radical are commercially available.

The derivatives of formula (V) for which R₆ represents a propyleneradical substituted in the 2-position by an alkyl radical may beobtained by application or adaptation of the method described by Y.Haramoto et al., J. Chem. Soc. Chem. Comm., 75 (1983).

The derivatives of formula (V) for which R₆ represents a propyleneradical substituted in the 2-position by an alkoxy radical may beobtained by application or adaptation of the method described in Can. J.Chem., vol. 48, 975 (1970).

The halogenated derivatives of formula (II) for which R₅ represents a═CH-- group, R₂ and R₃ represent a halogen atom and R₄ represents ahydrogen atom, and those for which R₂ and R₄ represent a hydrogen atomand R₃ represents a halogen atom and R₆ represents an alkylene (2-4 C)radical, may also be obtained by halogenation of a compound of formula(II) in which R₂, R₃ and R₄ represent a hydrogen atom and R₅ representsa ═CH-- group, then optional separation of the monohalogenatedderivative and the dihalogenated derivative.

The halogenation may be carried out by known methods such as thosedescribed by F. Dannerth et al., J. Am. Chem. Soc., 29, 1319 (1907), Th.Zincke et al., Ann. Chem., 411, 195 (1916) and A. Mustafa et al., Arch.Pharm., 298, 741 (1965).

The halogenated derivatives of formula (II) for which R₂, R₃, R₄ and R₅have the same meanings as in formula (I), and R₆ represents a propyleneradical substituted in the 1- or 3-position by an alkyl radical, withthe exception of those for which R₃ represents an acetylamino radical,may be obtained by halogenation of a hydroxylated derivative of formula:##STR6## in which R₂, R₃, R₄ and R₅ have the same meanings as above andR₇ represents a 3-hydroxypropyl radical substituted in the 1- or3-position by an alkyl radical.

This halogenation may be carried out according to processes known per sesuch as those described in MARCH, Advanced Organic Chemistry, p. 382(1985), Wiley Interscience.

This halogenation is preferably carried out by means of phosphorustribromide or trichloride, in an inert solvent such as toluene, benzeneor xylene, at a temperature of between 20° C. and the boiling point ofthe solvent.

The hydroxylated derivatives of formula (VII) may be prepared by theaction of a derivative of formula (IV) in which R₂, R₃, R₄ and R₅ havethe same meanings as in formula (VII), on a derivative of formula:

    Br--R.sub.7                                                (VIII)

in which R₇ has the same meanings as in formula (VII).

This reaction is generally carried out in the presence of a base such asan alkali-metal hydride, an alkali-metal hydroxide or an alkali-metalcarbonate, in an inert solvent such as acetonitrile, dimethylformamideor tetrahydrofuran, at a temperature of between 20° C. and the boilingpoint of the solvent.

The derivatives of formula (VIII) for which R₇ represents a3-hydroxypropyl radical substituted in the 1-position by an alkylradical may be prepared by application or adaptation of the methoddescribed by D. A. Palavandishvili et al., Chem. Abst., 70, 106089.

The derivatives of formula (VIII) for which R₇ represents a3-hydroxypropyl radical substituted in the 1-position by an alkylradical may be obtained by application or adaptation of the methoddescribed by F. Sato et al., Chem. lett., 99 (1980).

The halogenated derivatives of formula (II) for which R₂, R₃, R₄ and R₅have the same meanings as in formula (I), with the reservation that R₃cannot represent an acetylamino radical, and R₆ represents a propyleneradical substituted in the 2-position by an alkoxy radical may also beobtained by alkylation of the corresponding derivative of formula (II)for which R₆ represents a propylene radical substituted in the2-position by a hydroxy radical.

This alkylation may be carried out according to the processes known perse such as those described in MARCH, Advanced Organic Chemistry, 342(1985), Wiley Interscience.

For example an alkyl halide can be made to react in an inert solventsuch as dimethylformamide or tetrahydrofuran, in the presence of analkali-metal hydride or an alkali-metal carbonate, at a temperature ofbetween 20° C. and the boiling point of the solvent.

The halogenated derivatives of formula (II) for which R₅ represents a═CH-- group, R₂ and R₄ represent a hydrogen atom, R₃ represents anacetylamino radical and R₆ has the same meanings as above, may beprepared by N-acetylation of the corresponding amines.

The acetylation may be carried out by means of acetic anhydride, in thepresence of an alkali-metal acetate, at the boiling point of thereaction medium.

The corresponding amines may obtained by reduction of a derivative offormula: ##STR7## in which R₆ and Hal have the same meanings as informula (II).

This reduction is carried out, for example, by means of nickel chlorideand sodium borohydride, in an alcohol such as methanol or ethanol, at atemperature of about 0° C.

The nitrated derivatives of formula (IX) may be obtained by nitration ofa compound of formula (II) in which R₂, R₃ and R₄ represent a hydrogenatom and R₅ represents a ═CH-- group.

This nitration is generally carried out, preferably by means of nitricacid, at a temperature of about 0° C.

Compounds of formula (III) are available commercially or may be preparedby application or adaptation of the methods described by R. L. Duncan etal., J. Med. Chem., 13, 1 (1970); D. K. Yunk et al., J. Med. Chem., 21,1301 (1978); L. Nedelec et al., Eur. J. Med. Chem., 22, 33 (1987); J. P.Yevich et al., J. Med. Chem., 29, 3, 359 (1986); L. Thunus et al., Ann.Pharm., 38, 353 (1980); L. Gootes et al., Arzneim. Forsch., 17, 1145(1967) and J. Bergman et al., J. Het. Chem. 1071 (1970) and in PatentsDE 2139084, EP 110435 and U.S. Pat. Nos. 4,470,989 and 3,575,990 and ofthe methods described in the examples.

The 1-hydroxyphenylpiperazines may be obtained by demethylation of thecorresponding 1-methoxyphenylpiperazines by any method known to thoseversed in the art, and in particular by means of hydrobromic acid.

The compounds of formula (I) in which

either R₅ represents a ═CH-- group, and R₂, R₃ and R₄ represent ahydrogen atom, or R₂ and R₄ represent a hydrogen atom and R₃ representsa halogen atom, or R₂ and R₃ represent a hydrogen atom and R₄ representsa halogen atom, or R₂ and R₃ represent a halogen atom and R₄ representsa hydrogen atom,

or R₅ represents a nitrogen atom and R₂, R₃ and R₄ represent a hydrogenatom,

R₆ represents an alkylene (2-4 C) radical or a propylene radicalsubstituted in the 2-position by a hydroxy, alkyl or alkoxy radical,

except those for which R₁ is a 4-aminophenyl-1-piperazinyl radical, mayalso be prepared by the action of a compound of formula (IV) in whichR₂, R₃, R₄ and R₅ have the meanings mentioned above, on a derivative offormula:

    Hal--R.sub.6 --R.sub.1                                     (X)

in which R₆ and R₁ have the same meanings as above and Hal represents ahalogen atom.

This reaction is generally carried out in the presence of a base such asan alkali-metal hydride, an alkali-metal hydroxide or an alkali-metalcarbonate, in an organic solvent such as dimethylformamide ortetrahydrofuran, or in the presence of an alkali-metal hydroxide in anaqueous or hydro-organic medium, at a temperature of between 20° C. andthe boiling point of the solvent.

The derivatives of formula (X) may be prepared by the action of an alkyldihalide of formula (V) on a compound of formula (III).

This reaction is generally carried out in the presence of analkali-metal carbonate or a tertiary amine, in an organic solvent suchas acetonitrile, at a temperature of about 20° C.

The compounds of formula (I) for which R₆ represents a propylene radicalsubstituted in the 2-position by an alkoxy radical, with the exceptionof those for which R₁ represents a 1,2,3,6-tetrahydro-1-pyridyl radicalsubstituted in the 4-position by a 3-indolyl radical, a 3-indolylradical substituted in the 5-position by a hydroxy or hydroxyphenylradical, a 1-piperazinyl radical substituted in the 4-position by anamino or hydroxyphenyl radical or a piperidino radical substituted inthe 4-position by a 2-oxo-1-benzimidazolinyl, hydroxyphenyl, or hydroxyand phenyl radical optionally substituted by a hydroxy or 3-indolylradical optionally substituted in the 5-position by a hydroxy radicalmay also be obtained by alkylation of the corresponding compounds offormula (I) for which R₆ represents a propylene radical substituted inthe 2-position by a hydroxy radical.

This alkylation may be carried out under the same conditions as thosedescribed above for the alkylation of the halogenated derivatives offormula (II) for which R₆ represents a propylene radical substituted inthe 2-position by a hydroxy radical.

The compounds of formula (I) for which R₆ represents a propylene radicalsubstituted in the 2-position by a dialkylamino, piperidino, morpholinoor thiomorpholino radical may be obtained by the action of a brominatedderivative of formula: ##STR8## in which R₂, R₃, R₄, R₅ and R₁ have thesame meanings as in formula (I) on a derivative of formula:

    H--R.sub.8                                                 (XII)

in which R₈ represents a dialkylamino, piperidino, morpholino orthiomorpholino radical.

This reaction is generally carried out in an inert solvent such asbenzene, toluene or xylene, in the presence of a tertiary amine such astriethylamine, in a bomb at a temperature varying from 20° C. to theboiling point of the solvent.

The brominated derivatives of formula (XI) may be obtained bybromination of a corresponding derivative of formula (I) for which R₇represents a propylene radical substituted in the 2-position by ahydroxy radical.

This bromination is carried out under the same conditions as thosedescribed above for the bromination of compounds of formula (VII).

The compounds of formula (I) for which R₆ represents a propylene radicalsubstituted in the 3-position by a methyl radical, with the exception ofthose for which R₃ represents an acetylamino radical and/or R₁represents a substituent containing a hydroxy radical, may also beobtained by the action of a derivative of formula (IV) on a derivativeof formula: ##STR9## in which R₁ has the same meanings as above.

This reaction is generally carried out under the same conditions asthose mentioned above for the reaction of compounds of formula (IV) and(VII).

The derivatives of formula (XIII) may be obtained by bromination of aderivative of formula: ##STR10## in which R₁ has the same meanings asabove.

This bromination is preferably carried out under the same conditions asthose described above for the bromination of compounds of formula (VII).

The derivatives of formula (XIV) may be obtained by the action of3-bromo-1-butanol on a derivative of formula (III).

This reaction is generally carried out under the conditions describedabove for the reaction of derivatives of formulae (II) and (III).

The compounds of formula (I) for which R₁ represents a1,2,3,6-tetrahydro-1-pyridyl radical substituted in the 4-position by a3-indolyl radical substituted on the nitrogen atom by an alkyl oralkylcarbonyl radical, or a piperidino radical substituted in the4-position by a 2-oxo-1-benzimidazolinyl radical substituted in the3-position by an alkylcarbonyl or benzoyl radical, or a 3-indolylradical substituted on a nitrogen atom by an alkyl or alkylcarbonylradical, with the exception of those for which R₆ represents a propyleneradical substituted in the 2-position by a hydroxy radical, may beobtained by the action of a derivative of formula:

    Hal--R.sub.9                                               (XV)

in which Hal represents a halogen atom and R₉ represents an alkyl,alkylcarbonyl or benzoyl radical, on the corresponding derivatives offormula (I) for which R₁ represents a 1,2,3,6-tetrahydro-1-pyridylradical substituted in the 4-position by a 3-indolyl radical, or apiperidino radical substituted in the 4-position by a2-oxo-1-benzimidazolinyl or 3-indolyl radical.

This reaction is preferably carried out in an inert solvent such asdimethylformamide or tetrahydrofuran, at a temperature of between 20° C.and the boiling point of the solvent.

The compounds of formula (I) in which R₁ represents a1,2,3,6-tetrahydro-1-pyridyl radical substituted in the 4-position by aphenyl radical substituted by a halogen atom may also be obtained bydehydration of a corresponding compound of formula (I) for which R₁represents a 1,2,3,6-tetrahydro-1-pyridyl radical substituted in the4-position by a hydroxy radical and a phenyl radical substituted by ahalogen atom.

This dehydration may be carried out by known methods such as thosedescribed in MARCH, Advanced Organic Chemistry, 901 (1985), andparticularly by means of sulphuric acid or of an acetic acid-hydrobromicacid, acetic acid-hydrochloric acid mixture at a temperature of between20° C. and the boiling point of the reaction medium.

The compounds of formula (I) for which R₁ represents a4-aminophenyl-1-piperazinyl radical may be obtained by reduction of thecorresponding compounds of formula (I) for which R₁ represents a4-nitrophenyl-1-piperazinyl radical.

This reduction is generally carried out by means of stannous chlorideand sodium borohydride in an alcohol such as methanol or ethanol, in thepresence of water, at a temperature of between 20° C. and 70° C. bymeans of iron and hydrochloric acid in water or a water-alcohol mixture,at a temperature of between 20° C. and the boiling point of the reactionmedium.

Compounds of formula (I) may be purified by the standard known methodssuch as crystallization or chromatography.

Compounds of formula (I), in the form of the free base, may be convertedto addition salts with acids by the action of an acid in an organicsolvent such as an alcohol, a ketone, a chlorinated solvent or an ether.

The compounds of formula (I) and their salts have useful properties.These compounds have antagonist properties towards serotonin (5HT₂receptors) and are therefore useful for the treatment of ailments inwhich serotonin is implicated, and in particular ailments of the centralnervous system and the cardiovascular system and gastrointestinaldisorders.

These compounds are useful in particular for the treatment of anxiety,sleeping problems, depression, psychoses and in particularschizophrenia, migraine, asthma, hypertension and urticaria, asanalgesics and as inhibitors of platelet aggregation.

The affinity of the compounds of formula (I) for the central serotininreceptor sites (type S₂) has been determined according to a techniqueinspired by that of J. E. Leysen et al., Mol. Pharmacol., 21, 301(1982), which consists in measuring the affinity of the products for thebinding sites of tritiated ketanserin. In this test, the IC₅ 0 ofcompounds of formula (I) is generally less than 25 nM.

Compounds of formula (I) have low toxicity. They are generally atoxic at300 mg/kg orally in the mouse in a single administration.

The compounds of formula (I) in which R₁ represents a1,2,3,6-tetrahydro-1-pyridyl radical substituted in the 4-position by ahalophenyl radical, a phenylradical or a 3- indolyl radical substitutedon the nitrogen atom by alkyl or alkylcarbonyl radical, a 1-piperazinylradical substituted in the 4-position by a 2-pyridyl radical,1,2-benzisothiazol-3-yl radical or phenyl radical substituted by ahalogen atom or a hydroxy, amino or alkyl radical or a piperidinoradical substituted in the 4-position by a phenyl or N-alkyl-3-indolylradical are particularly interesting.

The following products are of particular interest:

2-{3-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]propyl}-naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(4-aminophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(3-fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(4-methylphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(3-hydroxyphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(1-methyl-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(1-acetyl-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]naphtho}[1,8-cd]isothiazole1,1,dioxide

2-{2-[4-(4-hydroxyphenyl)-1-piperazinyl]ethyl}naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide

2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(4-fluorophenyl)-1,2,3,6-tetrahydro-1-pyridyl]-propyl}naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(2-pyridyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide

2-[3-(4-phenyl-1-piperidino)propyl]naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(4-hydroxyphenyl)-1-piperazinyl]propyl)naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxypropyl}naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-methoxypropyl}naphtho[1,1-d]isothiazole1,1-dioxide

2-{2-dimethylamino-3-[4-(4-fluorophenyl)-1-(piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide

2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-methylpropyl}naphtho[1,8-cd]isothiazole1,1-dioxide

2-{3-[4-(4-fluorophenyl)-1-piperazinyl]butyl}naphtho[1,8-cd]isothiazole1,1-dioxide

2-{4-[4-(4-fluorophenyl)-1-piperazinyl]-2-butyl}naphtho[1,8-cd]isothiazole1,1-dioxide.

For therapeutic use, compounds of formula (I) can be used as such or inthe state of pharmaceutically acceptable salts.

Addition salts with inorganic acids, such as hydrochlorides, sulphates,nitrates or phosphates, or organic acids such as acetates, propionates,succinates, benzoates, fumarates, maleates, methanesulphonates,isothionates, theophyllineacetates, salicylates, phenolphthalinated ormethylene-bis-β-oxynaphthoates, or substitution derivatives of thesederivatives, may be mentioned in particular as pharmaceuticallyacceptable salts.

EXAMPLES

The following examples illustrate the invention.

EXAMPLE 1

2-(3-Chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (28.1 g),triethylamine (14 cc) and 1-(4-fluorophenyl)piperazine (18.8 g) intoluene (300 cc) are heated for 8 hours at boiling point. The mixture isthen cooled to a temperature of about 20.C and stirring is maintainedfor 15 hours at this temperature. The precipitate formed is separated byfiltration and washed with toluene (2×50 cc). The filtrate is evaporatedto dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). Theresidue obtained is purified by flash-chromatography on a silica column,under a current of argon at medium pressure (0.1-1.5 bar) with ethylacetate as eluant, and recrystallized from boiling acetonitrile (150cc).2-{3-[4-(4-Fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide is obtained, m.p. 95°-97° C.

2-(3-Chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide may be preparedin the following manner: a solution of b 1,8-naphthosultam (175 g) indimethylformamide (2100 cc) is poured, over 3 hours and 30 minutes, intoa 50% dispersion of sodium hydride (40.2 g) in vaseline oil, under acurrent of argon, maintaining the temperature between 20° C. and 30° C.The reaction medium is stirred for 1 hour at a temperature of about 20°C., and then 1-bromo-3-chloropropane (83 cc) is added over 10 minutes.Stirring is maintained for 15 hours at a temperature of about 20° C. Thereaction mixture is concentrated to dryness at 50° C. under reducedpressure (0.5 mm Hg; 0.07 kPa). The residue is purified bychromatography on a silica column with a mixture of dichloromethane andcyclohexane (60-40 vol) as eluant.2-(3-Chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (165.7 g) isobtained, m.p. 78° C.

EXAMPLE 2

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.8 g),triethylamine (1.4 cc) and 4-phenyl-1,2,3,6-tetrahydropyridine (1.6 g)in toluene (30 cc). The mixture is heated for 8 hours at boiling point,then cooled to a temperature of about 20° C. Stirring is continued for15 hours at this temperature. After purification by flash-chromatographyon a silica column, under a current of argon at medium pressure (0.5-1.5bar) with ethyl acetate as eluant, and recrystallization from boilingisopropanol (2 cc),2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]naphtho[1,8-cd]isothiazole1,1-dioxide (1.5 g) is obtained, m.p. 88° C.

EXAMPLE 3

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (100 g),triethylamine (50 cc) and 4-(4-fluorophenyl) 1,2,3,6-tetrahydropyridine(77.9 in toluene (950 cc). The mixture is heated for 7 hours at boilingpoint, then cooled to a temperature of about 20° C. Stirring iscontinued for 8 hours at this temperature. After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with ethyl acetate as eluant,2-{3-[4-(4-fluorophenyl)-1,2,3,6-tetrahydro-l-pyridyl]propyl}-naphtho[1,8-cd]isothiazole1,1-dioxide (105.4 g) is obtained in the form of a brown oil [Rf=0.8;thin-layer chromatography on silica gel; eluant: ethyl acetate]. Thisoil is converted to the hydrochloride, m.p. 224° C.

EXAMPLE 4

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.5 g),triethylamine (4.2 cc) and 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine(5.7 g) in toluene (80 cc). The mixture is heated for 8 hours at boilingpoint, then cooled to a temperature of about 20° C. Stirring iscontinued for 8 hours at this temperature. After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with ethyl acetate as eluant, andrecrystallization from boiling acetonitrile (50 cc),2-{3-[4-(4-chlorophenyl)-1,2,3,6-tetrahydro-l-pyridyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (4.9 g) is obtained, m.p. 111° C.

EXAMPLE 5

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]-isothiazole 1,1-dioxide (8.5 g),triethylamine (4.2 cc) and 1-(2-pyridyl)piperazine (4.7 cc) in toluene(8cc). The mixture is heated for 2 hours at boiling point, then cooledto a temperature of about 20° C. After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with ethyl acetate as eluant, andrecrystallization from boiling acetonitrile (30 cc),2-{3-[4-(2-pyridyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (4.2 g) is obtained, m.p. 101° C.

EXAMPLE 6

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.5 g),triethylamine (4.2 cc) and N-phenylpiperazine (4.8 cc) in toluene (80cc). The mixture is heated for 8 hours at boiling point, then cooled toa temperature of about 20° C. After purification by flash-chromatographyon a silica column, under a current of argon at medium pressure (0.5-1.5bar) with ethyl acetate as eluant, and recrystallization from boilingacetonitrile (30 cc),2-[3-(4-phenyl-l-piperazinyl)propyl]naphtho[1,8-cd]isothiazole1,1-dioxide (5.7 g) is obtained, m.p. 126° C.

EXAMPLE 7

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.5 g),triethylamine (4.2 cc) and 4-phenylpiperidine (4.9 g) in toluene (80cc). The mixture is heated for 8 hours at boiling point, then cooled toa temperature of about 20° C. Stirring is continued for 15 hours at thistemperature. After purification by flash-chromatography on a silicacolumn, under a current of argon at medium pressure (0.5-1.5 bar) withethyl acetate as eluant, and recrystallization from boiling acetonitrile(30 cc), 2-[3-(4-phenyl-l-piperidino)propyl]naphtho[1,8-cd]isothiazole1,1-dioxide (7.1 g) is obtained, m.p. 125° C.

EXAMPLE 8

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (70.3 g),triethylamine (105 cc) and 1-(4-hydroxyphenyl)piperazine dihydrobromide(85.2 g) in dimethylformamide (2100 cc). The mixture is heated for 8hours at boiling point, then cooled to a temperature of about 20° C.Stirring is continued for 6 hours at this temperature. Afterpurification by flash-chromatography on a silica column, under a currentof argon at medium pressure (0.5-1.5 bar) with dichloromethane and thena mixture of dichloromethane and ethyl acetate (5-50 vol) as eluant, andrecrystallization from boiling acetonitrile (1150 cc),2-{3-[4-(4-hydroxyphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (20.5 g) is obtained, m.p. 185° C.

1-(4-Hydroxyphenyl)piperazine dihydrobromide may be prepared in thefollowing manner: a 47% aqueous solution of hydrobromic acid (720 cc) isadded, over 30 minutes and at a temperature of about 20° C., to4-(4-methoxyphenyl)piperazine dihydrochloride (70 g). The mixture isheated at boiling point for 4 hours then cooled to a temperature ofabout 20° C. Stirring is continued for 15 hours at this temperature,then the mixture is concentrated at 40° C. under reduced pressure (20 mmHg; 2.7 kPa). The residual oil is redissolved in acetonitrile (300 cc).The precipitate formed is separated by filtration, washed withacetonitrile (2×50 cc) and diisopropyl ether (2×100 cc).4-(4-Hydroxyphenyl)260° C.) is obtained and used in the crude state inthe subsequent syntheses.

EXAMPLE 9

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (4.2 g),triethylamine (2.1 cc), sodium iodide (2.2 g) and4-(4-fluorobenzoyl)piperidine (3.1 g) in dimethylformamide (50 cc). Themixture is heated for 8 hours at boiling point, then cooled to atemperature of about 20° C. Stirring is continued for 7 hours at thistemperature. After purification by flash-chromatography on a silicacolumn, under a current of argon at medium pressure (0.5-1.5 bar) withethyl acetate as eluant, and recrystallization from boiling acetonitrile(15 cc),2-{3-[4-(4-fluorobenzoyl)piperidino]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.65 g) is obtained, m.p. 132° C.

4-(4-Florobenzoyl)piperidine may be prepared according to the methoddescribed by R. L. Duncan et al., J. Med. Chem., 13, 1 (1970).

EXAMPLE 10

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.3 g),triethylamine (2.6 cc), 4-(4-chlorophenyl) piperazine (5 g) and sodiumiodide (2.8 g) in toluene (50 cc). The mixture is heated for 6 hours atboiling point, then cooled to a temperature of about 20° C. Afterrecrystallization, firstly from boiling acetonitrile 6 hours andsecondly from boiling methyl ethyl ketone (15 cc),2-{3-[4-(4-chlorophenyl)-1-piperazinyl ]propyl}naptho[1,8-cd]isothiazole1,1-dioxide (3 g) is obtained, m.p. 120° C.

EXAMPLE 11

The experiment is carried out as in Example 1, starting with2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.5 g),triethylamine (3.4 cc) and 4-phenyl-1,2,3,6-tetrahydropyridine (3.9 g)in toluene (150 cc). The mixture is heated for 9 hours at boiling point,then cooled to a temperature of about 20° C. After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with dichloromethane as eluant, andrecrystallization from boiling acetonitrile (10 cc),2-[2-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)ethyl]naphtho[1,8-cd]isothiazole1,1-dioxide (2.5 g) is obtained, m.p. 106° C.

2-(2-Chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide may be preparedin the following manner: the experiment is carried out as in Example 1for the preparation of 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole1,1-dioxide, starting with sodium hydride (4.8 g) in a 50% dispersion invaseline oil, 1-bromo-2-chloroethane (8.8 cc) and 1,8-naphthosultam(20.5 g) in dimethylformamide (250 cc). After purification byflashchromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with a mixture of dichloromethane andcyclohexane (70-30 vol) as eluant,2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (20.7 g) isobtained, m.p. 96° C.

EXAMPLE 12

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.8 g),triethylamine (2.8 cc) and 4,4-diphenylpiperidine hydrochloride (2.7 intoluene (30 cc). The mixture is heated for 8 hours at boiling point,then cooled to a temperature of about 20° C. Stirring is continued for 7hours at this temperature. After purification by flash-chromatography ona silica 1.5 bar) with ethyl acetate as eluant, and recrystallizationfrom boiling acetonitrile (10 cc),2-[3-(4,4-diphenylpiperidino)propyl]naphtho[1,8-cd]isothiazole1,1-dioxide (1.6 g) is obtained, m.p. 168° C.

4,4-Diphenylpiperidine hydrochloride may be prepared according to themethod described in German Patent 2139084.

EXAMPLE 13

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.6 g),triethylamine (2.8 cc) and 4-(4-bromophenyl)piperazine (4.8 g) intoluene (60 cc). The mixture is heated for 8 hours at boiling point,then cooled to a temperature of about 20° C. Stirring is continued for 8hours at this temperature. After purification by flash-chromatography ona silica column, under a current of argon at medium pressure re (0.5-1.5bar) with ethyl acetate as eluant, and recrystallization from boilingacetonitrile (40 cc),2-{3-[4-(4-bromophenyl)-1-piperazinyl]propyl)naphtho[1,8-cd]isothiazole1,1-dioxide (4.3 g) is obtained, m.p. 149° C.

4-(4-Bromophenyl)piperazine dihydrochloride may be prepared according tothe method described by D. K. Yung, J. Med. Chem., 21, 1301 (1978).

EXAMPLE 14

The experiment is carried out as in Example 1, starting with2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.7 g),triethylamine (3.5 cc), 4-(4-fluorobenzoyl)piperidine (5.2 g) and sodiumiodide (3.7 g) in dimethylformamide (100 cc). The mixture is heated for6 hours at boiling point, then cooled to a temperature of about 20° C.After purification by flash-chromatography on a silica column, undercurrent of argon at medium pressure (0.5-1.5 bar) with dichloromethaneas eluant, and recrystallization from boiling acetonitrile (8 cc),2-{2-[4-(4-fluorobenzoyl)piperidino}ethyl)naphtho[1,8-cd]isothiazole1,1-dioxide (2.9 g) is obtained, m.p. 145° C.

EXAMPLE 15

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (9.3 g),triethylamine (4.6 cc) and 4-(3-indolyl)-1,2,3,6-tetrahydropyridine (6.5g) in dimethylformamide (100 cc). The mixture is heated for 8 hours atboiling point, then cooled to a temperature of about 20° C. Stirring iscontinued for 7 hours at this temperature. After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with ethyl acetate as eluant, 2.9 g of ayellow solid are obtained, which is purified by flash-chromatography ona silica column, under a current of argon at medium pressure (1.5-1.5bar) with a mixture of dichloromethene and methnol (90-10 vol) aseluant, and recrystallization from boiling acetonitrile (40 cc).2-{3-[4-(3-Indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (2.1 g) is obtained, m.p 226° C.

4-(3-Indolyl-)-1,2,3,6-tetrahydropyridine may be prepared according tothe methol described by L. Nedelec et al., Eur. J. Med. Chem., 22, 33(1987).

EXAMPLE 16

The experiment is carried out as in Example 1, starting with2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (10 g),triethylamine (4.8 cc) and 4-phenyl-1,2,3,6-tetrahydropyridine (5.4 g)in toluene (300 cc). The mixture is heated for 9 hours at boiling point,then cooled to a temperature of about 20° C. After purification byflash-chromatography on silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with ethyl acetate as eluant, andrecrystalline from boiling acetonitrile (10 cc),2-[4-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)butyl]naphtho[1,8-cd]isothiazole1,1-dioxide (2.6 g) is obtained, m.p. 101° C.

2-(4-Chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide may be obtainedin the following manner: operating as in Example 1 for the preparationof 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide, startingwith sodium hydride (4.8 g) in a 50% dispersion in vaseline oil,1-bromo-4-chlorobutane (11.9 cc) and 1,8-naphthosultam (20.5 indimethylformamide (250 cc). After purification by flash-chromatographyon a silica under a current of argon at medium pressure (0.5-1.5 bar)with a mixture of dichloromethane and cyclohexanone (30-70 vol) aseluant, 2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (24.6 g)is obtained in the form of a yellow oil which is used in the crude statein the subsequent syntheses.

EXAMPLE 17

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]-isothiazole 1,1-dioxide (3.9 g),triethylamine (1.9 cc), 4-[bis(4-fluorophenyl)methylene]piperidine (3.7g) and sodium iodide (2.1 g) in toluene (150 cc). The mixture is heatedfor 6 hours at boiling point, then cooled to a temperature of about 20°C. After purification by flashchromatography on a silica column, under acurrent of argon at medium pressure (0.5-1.5 bar) with dichlorometheneas eluant,2-{3-[bis(4-fluorophenyl)-4-methylenepiperiino]propylynaphtho[1,8-cd]-isothiazole1,1-dioxide (4.6 g) is obtained in the form of a brown oil which isconverted to the hydrochloride, m.p. 137° C.

4-[bis(4-Fluorophenyl)methylene]piperidine maybe prepared according tothe method described in European Patent 110 435.

EXAMPLE 18

Dimethylformamide (20 cc) is added to sodium hydride (0.6 g) in an 80%dispersion in vaseline oil, under current of argon. The suspensionobtained is stirred, then a solution of5-bromonaphtho[1,8-cd]isothiazole 1,1-dioxide (5.7 g) indimethylformamide (30 cc) is poured in drop by drop, over 15 minutes,maintaining the temperature between 20° C. and 30° C. The reactionmedium is stirred for 15 minutes at a temperature of about 20° C., thena solution of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine(4.7 g) in dimethylformamide (20 cc) is poured in drop by drop, over 10minutes, at a temperature of about 20° C. The reaction medium is heatedfor 1 hour at 100° C., then cooled to a temperature of about 20° C. Thereaction mixture is redissolved in distilled water (300 cc) andextracted with ethyl acetate (200 cc). After washing with distilledwater (3×50 cc), the organic extract is dried over magnesium sulphateand concentrated to dryness at 40° C. under reduced pressure (20 mm Hg;2.7 kPa). After recrystallization from boiling acetonitrile (110 cc)5-bromo-2-[3-(4-phenyl-1,2,3,6-tetrahydro-l-pyridyl)propyl]naphtho[1,8-cd]isothiazole1,1-dioxide (5.3 g) is obtained, m.p. 138° C.

1-(3-Chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine may be preparedin the following manner: 4-phenyl-1,2,3,6-tetrahydropyridine (41 g),1-bromo-3-chloropropane (100 cc), potassium carbonate (140 g) andacetonitrile (600 cc) are stirred for 12 hours at a temperature of about20° C. After filtration, the solution is concentrated to dryness at 40°C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purifiedby chromatography on a silica column with a mixture of cyclohexane andethyl acetate (60-40 vol) as eluant.1-(3-Chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine (48 is obtainedin the form of an oil.

5-Bromonaphtho[1,8-cd]isothiazole 1,1-dioxide may be obtained accordingto the process described by A. MUSTAFA et al., Arch. Pharm., 298, 741,(1965).

EXAMPLE 19

5-Acetylamino-2-(3-chloropropyl)naphto[1,8-cd]isothiazole 1,1-dioxide(0.8 g), 4-phenyl-1,2,3,6-tetrahydropyridine (0.4 g), potassiumcarbonate (4 g) and acetonitrile (25 cc) are heated at boiling point for20 hours. The reaction mixture is cooled to a temperature of about 20°C. The solution is filtered and then concentrated to dryness at 40° C.under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified bychromatography on silica column with a mixture of ethyl acetate andmethylene chloride (70-30 vol) as eluant, then recrystallized fromboiling ethanol (20 cc).5-acetylamino-2-[3-(4-phenyl-1,2,3,6-tetrahydro-l-pyridyl)propyl]naphtho[1,8-cd]isothiazole1,1-dioxide (0.35 g) is obtained, m.p. 178° C.

5-Acetylamino-2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxidemay be prepared in the following manner:5-amino-2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.1g), sodium acetate (0.2 g) and acetic anhydride (15 cc) are heated atboiling point for 30 minutes. The reaction mixture is cooled to atemperature of about 20° C., treated with distilled water (5 cc) andheated at boiling point for 15 minutes. The mixture is cooled to atemperature of about 20° C., then concentrated to dryness at 50° C.under reduced pressure (0.5 mm Hg; 0.07 kPa). The residue is redissolvedin dichloromethane (100 cc) and the solution is washed with distilledwater (40 cc), dried over magnesium sulphate, then concentrated todryness at 20° C. under reduced pressure (20 mm Hg; 2.7 kPa). Afterrecrystallization from boiling chloroform (15 cc),5-acetylamino-2-(3-chloropropyl)naphtho[1,8-cd] isothiazole 1,1-dioxide(0.6 g) is obtained, m.p. 205° C.

5-Amino-2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide may beprepared in the following manner: sodium borohydride (3.8 g) is preparedin small quantities, over one hour, to a solution of5-nitro-2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (12.2g) and nickel chloride with 6 water molecules (18 g) in methanol (600cc), at a temperature of about 0° C. The reaction mixture is stirred forone hour at this temperature, then concentrated to dryness at 40° C.under reduced pressure (20 mm Hg; 2.7 kPa). The residue is redissolvedin 1 N hydrochloric acid (50 cc), then treated with a 3 N ammoniasolution (100 cc). The mixture is extracted with dichloromethane (500cc). The organic extract is dried over magnesium sulphate andconcentrated to dryness at 20° C. under reduced pressure (20 mm Hg; 2.7kPa). The residue is purified by chromatography on a silica column withdichloromethane as eluant.5-Amino-2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3.4 g)is obtained in the form of an oil.

5-Nitro-2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide may beprepared in the following manner:2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (12 g),obtained as in Example 1, is added, over 5 minutes, to a 66.97% solutionof nitric acid (d=1.4) (50 cc), at a temperature of about 0° C. Thereaction mixture is stirred for one hour at this temperature, thentreated with distilled water (150 cc) and stirred for a further 15minutes. The precipitate is filtered, washed with distilled water (3 x50 cc) then dried in air.5-Nitro-2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (12.2g) is obtained and used in the crude state in the subsequent syntheses.

EXAMPLE 20

The experiment is carried out as in Example 18, starting with5-chloronaphtho[1,8-cd]isothiazole 1,1-dioxide (1.2 g), sodium hydride(0.15 in an 80% dispersion in vaseline oil, 1-(3-chloropropyl)-4-phenyl1,2,3,6-tetrahydropyridine (1.4 g), obtained as in Example 18, anddimethylformamide (30 cc). The reaction mixture is heated for one hourat 70° C., cooled to a temperature of about 20° C. then concentrated todryness at 20° C. under reduced pressure (0.5 mm Hg; 0.07 kPa). Theresidue is redissolved in dichloromethane (100 cc) and the solution iswashed with distilled water (50 cc), dried over magnesium sulphate andconcentrated to dryness at 20.C under reduced pressure (20 mm Hg; 2.7kPa). The residue is purified by chromatography on a silica column witha mixture of dichloromethane and ethyl acetate (90-10 vol) as eluant,and recrystallized from boiling acetonitrile (30 cc).5-Chloro-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]naphtho[1,8-cd]isothiazole1,1-dioxide (1 g) is obtained, m.p. 135° C.

5-Chloronaphtho[1,8-cd]isothiazole 1,1-dioxide may be obtained accordingto the process described by A. MUSTAFA et al., Arch. Pharm., 298, 741,(1965).

5-Chloro-2-[3-(4-phenyl-1,2,3,6-tetrahydro-1-pyridyl)propyl]naphtho[1,8-cd]isothiazole1,1-dioxide may also be prepared in the following manner: the experimentis carried out as in Example 19, starting with5-chloro-2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3.2g), 4-phenyl-1,2,3,6-tetrahydropyridine (1.8 g), potassium carbonate (12g) and acetonitrile (125 cc). The reaction mixture is heated at boilingpoint for 5 hours, then cooled to a temperature of about 20° C. Afterfiltration and concentration to dryness at 40° C. under reduced pressure(20 mm Hg; 2.7 kPa), the residue is purified by chromatography on asilica column with a mixture of dichloromethane and ethyl acetate (85-15vol) as eluant, and recrystallized from boiling acetonitrile (40 cc).5-Chloro-2-[3-(4-phenyl-1,2,3,6-tetrahydro-l-pyridyl)propyl]naphtho[1,8-cd]isothiazole1,1-dioxide (2.8 g) is obtained, m.p. 135° C.

5-Chloro-2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide may beobtained in the following manner: a solution of chlorine (5.4 g) inacetic acid (100 cc) is poured drop by drop, over 15 minutes, into asolution of 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (18g), obtained as in Example 1, in acetic acid (200 cc) at a temperatureof about 0° C. The reaction mixture is stirred for 24 hours at atemperature of about 20° C., then concentrated to dryness at 60° underreduced pressure (20 mm Hg; 2.7 kPa). The residue is purified bychromatography on a silica column with a mixture of dichloromethane andcyclohexane (50-50 vol) as eluant.3,5-Dichloro-2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide(1.7 g), m.p. 164° C., and5-chloro-2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3.2g), m.p. 80° C., are obtained.

EXAMPLE 21

The experiment is carried out as in Example 19, startingwith3,5-dichloro-2-(3-chloropropyl)naphtho[1,8-cd] isothiazole1,1-dioxide (1.7 g) obtained as in Example 20,4-phenyl-1,2,3,6-tetrahydropyridine (0.85 g), potassium carbonate (7 g)and acetonitrile (90 cc). The reaction mixture is heated at boilingpoint for 20 hours, then cooled to a temperature of about 20° C. Thesolution is filtered and then concentrated to dryness at 40° C. underreduced pressure (20 mm Hg; 2.7 kPa). The residue is recrystallized fromboiling acetonitrile (25 cc).3,5-Dichloro-2-[3-(4-phenyl-1,2,3,6-tetrahydro-l-pyridyl)propyl]naphtho[1,8-cd]isothiazole1,1-dioxide (1 g) is obtained, m.p. 126° C.

EXAMPLE 22

The experiment is carried out as in Example 18, starting with6-chloronaphtho[l,8-cd]isothiazole 1,1-dioxide (1.4 g),1-(3-chloropropyl)-4-(4-fluorophenyl)piperazine (1.5 g), sodium hydride(0.18 g) in an 80% dispersion in vaseline oil and dimethylformamide (15cc). The reaction mixture is heated for 1 hour 30 minutes at 90° C.,cooled to a temperature of about 20° C. and then concentrated to drynessat 60° C. under reduced pressure (0.5 mm Hg; 0.07 kPa). The residue isredissolved in dichloromethane (50 cc) and the solution is washed withdistilled water (20 cc), dried over magnesium sulphate and concentratedto dryness at 20° C. under reduced pressure (20 mm Hg; 2.7 kPa). Theresidue is purified by chromatography on a silica column with mixture ofdichloromethane and ethyl acetate (95-5 vol) as eluant, thenrecrystallized from boiling acetonitrile (10 cc).6-Chloro-2-{3-[4-(4-fluorophenyl)-l-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.2 is obtained, m.p. 125° C.

6-Chloronaphtho[1,8-cd]isothiazole 1,1-dioxide may be prepared in thefollowing manner: 8-amino-4-chloro-1-naphthalenesulfonic acid (13.3 g)and phosphorus oxychloride (30 cc) are heated at boiling point for 3hours. The reaction mixture is then cooled to a temperature of about 0°C., and then treated with distilled water (100 cc). The precipitate isisolated by filtration, washed with distilled water (3×20 cc) andextracted with chloroform (3×150 cc). The organic extracts are driedover magnesium sulphate and concentrated to dryness at 40° C. underreduced pressure (20 mm Hg; 2.7 kPa). Crude6-chloronaphtho[1,8-cd]isothiazole 1,1-dioxide (1.4 g) is obtained,which is used as such in the subsequent syntheses.

8-Amino-4-chloro-l-naphthalenesulphonic acid may be prepared accordingto the process described by P. FRIEDLANDER et al., Chem. Ber., 55B, 45,(1922).

1-(3-Chloropropyl)-4-(4-fluorophenyl)piperazine may be prepared in thefollowing manner: the experiment is carried out as in Example 18 for1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine, starting with1-(4-fluorophenyl)piperazine (50 g), 1-bromo-3-chloropropane (68 cc),sodium carbonate (97 g) and acetonitrile (400 cc). The reaction mixtureis stirred for 12 hours at a temperature of about 20° C. and thesolution is filtered and then concentrated to dryness at 40° C. underreduced pressure (20 mm Hg; 2.7 kPa). The residue is purified bychromatography on a silica column with ethyl acetate as eluant.1-(3-Chloropropyl)-4-(4-fluorophenyl)piperazine (44.4 g) is obtained inthe form of an oil.

EXAMPLE 23

A solution of 1-(3-chloropropyl)-4-phenyl-1,2,3,6-tetrahydropyridine(4.9 g) in dimethylformamide (20 cc) is added to a solution of thesodium salt of 2H-isothiazolo[3,4,5-de]isoquinoline 1,1-dioxide(obtained by heating, after the evolution of gas has ceased, a solutionof 4-bromo-5-isoquinolylsulphonamide (4.1 g) in dimethylformamide (25cc) and a suspension of sodium hydride (0.85 g) in an 80% dispersion invaseline oil in dimethylformamide (50 cc) at 110° C. for 2 hours and 30minutes) cooled to 20° C. The reaction medium is heated for 2 hours at100° C., then poured into a mixture of water (300 cc) and ethyl acetate(300 cc). The organic phase is washed with water (3×300 cc), dried overmagnesium sulphate and concentrated to dryness. The residue is purifiedby chromatography on a silica column under a slight overpressure ofnitrogen, eluting with ethyl acetate and then with a mixture of ethylacetate and ethanol vol).2-[3-(4-Phenyl-1,2,3,6-tetrahydropyridyl)propyl]-2H-isothiazolo[3,4,5-de]isoquinoline1,1-dioxide (1.4 g) is obtained in the form of a yellow oil. 1.8 g ofthis product are purified with a second, similar chromatography stage togive2-[3-(4-phenyl-1,2,3,6-tetrahydropyridyl)propyl]-2H-isothiazolo[3,4,5-de]isoquinoline1,1-dioxide (1.6 g) (Rf =0.27; support: silica gel; eluant: ethylacetate-ethanol (9-1 vol)). This product is dissolved in ethyl acetate(100 cc) before adding a 3 N solution of hydrochloric acid in isopropyloxide (5 cc). The precipitate is centrifuged, washed with ethyl acetateand dried under vacuum (0.1 mm Hg) at 35° C.2-[3-(4-Phenyl-1,2,3,6-tetrahydropyridyl)propyl]-2H-isothiazolo[3,4,5-de]isoquinoline1,1-dioxide dihydrochloride (1.6 g) is obtained in the form of a yellow(amorphous) solid.

4-Bromo-5-isoquinolylsulphonamide may be obtained in the followingmanner: ammonia is bubbled into dry tetrahydrofuran at -50° C. untilsaturation. This solution is treated with a suspension of4-bromo-5-isoquinolylsulphonyl chloride (8 g) in tetrahydrofuran (50cc). The reaction mixture is left to return progressively to 20° C. Theprecipitate formed is Centrifuged, washed with tetrahydrofuran (3×10cc), water (3×30 cc) and ethyl acetate (2 x 10 cc), then centrifuged anddried. 4-Bromo-5-isoquinolylsulphonamide (4.5 g) is obtained in the formof a beige solid the m.p. of which is greater than 270° C.

4-Bromo-5-isoquinolylsulphonyl chloride may be obtained by the followingprocess: a solution of 5-amino- 4-bromoisoquinoline (4.46 g) inconcentrated hydrochloric acid (d=1.19) (44 cc) is cooled to -5° C. thenis treated with a solution of sodium nitrite (1.93 g) in water (10 cc).The reaction mixture is stirred for 1 hour at 0° C. The solutionobtained is poured into a saturated solution of sulphur dioxide inacetic acid (48 ml), to which has been added a solution of cuprouschloride (0.65 g) in water (5.6 cc). The reaction mixture is stirreduntil the evolution of gas has finished, and then is extracted withdichloromethane (2×100 cc). The organic phases are pooled, washed withwater, dried over magnesium sulphate and concentrated.4-Bromo-5-isoquino lylsulphonyl chloride (5.6 g) is obtained in the formof a yellow solid which is used as such in the subsequent syntheses.

5-Amino-4-bromoisoquinoline may be prepared in the following manner: asuspension of 4-bromo-5-nitroisoquinoline (25.3 g) in 2 N hydrochloricacid (180 cc) is progressively added to a solution of stannous chloride(90 g) in concentrated hydrochloric acid (d 1.19) (10cc). The reactionmixture is heated under reflux for 90 minutes, then is cooled and pouredinto a 2 N caustic soda solution (2 1), stirring and cooling to 0° C.The precipitate is washed with water, centrifuged and dried.5-Amino-4-bromoisoquinoline (21.6 g) is obtained in the form of yellowcrystals, m.p. 155° C.

4-Bromo-5-nitroisoquinoline may be obtained by the process described byM. D. Nair et al., Indian J. Chem. Soc., 5, 224 (1967).

EXAMPLE 24

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (12 g),triethylamine (6 cc) and 4-(4-hydroxyphenyl)-1,2,3,6-tetrahydropyridine(7.5 g) in dimethylformamide (120 cc). The mixture is heated for 8 hoursat boiling point, then cooled to a temperature of about 20° C. Stirringis continued for 12 hours at this temperature. After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with ethyl acetate as eluant, andrecrystallization from boiling acetonitrile (80 cc),2-{3[4-(4hydroxyphenyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide

(3 3 g) is obtained, m.p. 198° C.

4-(4-Hydroxyphenyl)-1,2,3,6-tetrahydropyridine may be prepared in thefollowing manner: a 35% solution of hydrobromic acid in acetic acid (250cc) is added, over 1 hour and at a temperature of about 5° C., to N-ben-zyloxycarbonyl-4-hydroxy-4-(4-methoxyphenyl)piperidine (21 g). Themixture is stirred for 1 hour at a temperature of about 20° C., then theaqueous phase is washed with diethyl ether (3×50 After decantation, theaqueous phase is redissolved in water (250 cc) and alkalinized with 10Ncaustic soda to pH 10. After extraction with dichloromethane (4×500 cc),the precipitate formed is separated by filtration.4-(4-Hydroxyphenyl)-1,2,3,6-tetrahydropyridine (7.5 g) is thus obtained,m.p. 245° C.

N-Benzyloxycarbonyl-4-hydroxy-4-(4-methoxyphenyl)piperidine may beprepared in the following manner: p-bromoanisole (1 cc) and a fewcrystals of iodine are added, at a temperature of about 20° C. and undera current of argon, to magnesium turnings (9.3 g) in diethyl ether (150cc). After 5 minutes, the solvent in the reaction medium is under refluxand a solution of p-bromoanisole (24.7 cc) in diethyl ether (300 cc) isadded over 1 hour in such a manner as to maintain the refluxing of thesolvent. Stirring is continued for 30 minutes at this temperature then,after cooling the

mixture to a temperature of about 20° C., a solution ofN-benzyloxycarbonyl-4-piperidone (48.2 g) in ethyl ether (450 cc) ispoured in. Stirring is continued for 15 hours at this temperature. Thereaction medium is then hydrolysed with a saturated solution of ammoniumchloride to pH 6-7, the extracted with diethyl ether (3×500 cc). Theorganic phase is dried over anhydrous magnesium sulphate andconcentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa). Theresidual oil is purified by flash-chromatography on a silica column,under a current of argon at medium pressure (0.5-1.5 bar) withdichloromethane and then a mixture of dichloromethane and methanol(90-10 vol) as eluant.N-Benzyloxycarbonyl-4-hydroxy-4-(4-methoxyphenyl)piperidine (21.2 g),m.p. 98° C. is thus obtained, which is used in the crude state in thesubsequent syntheses.

N-Benzyloxycarbonyl-4-piperidone may be prepared according to the mannerdescribed H. STETTER et al., Chem. Ber. 105, 2773 (1972).

EXAMPLE 25

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.74 9),triethylamine (3.4 cc) and4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (4.5 g) indimethylformamide (70 cc). The mixture is heated for 8 hours at boilingpoint, then cooled to a temperature of about 20° C. Stirring iscontinued for 12 hours at this temperature. After purification byflash-chromatography on silica gel, under a current of argon at mediumpressure (0.5-1.5 bar) with ethyl acetate as eluant, andrecrystallization from boiling acetonitrile (60 cc),2-{3-[4-(4-methoxyphenyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphthol[1,8-cd]isothiazole1,1-dioxide (2 g) is obtained, m.p. 178° C.

EXAMPLE 26

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (75 g),triethylamine (37.5 cc) and 4-(4-nitrophenyl)piperazine (55.3 cc) intoluene (600 cc). The mixture is heated for 10 hours at boiling point,then cooled to a temperature of about 20° C. After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with a mixture of dichloromethane andethyl acetate as eluant (80-20 vol), and recrystallization from boilingmethyl ethyl ketone (1100 cc),2-{3-[4-(4-nitrophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide(41.8 g) is obtained, m.p. 186° C.

EXAMPLE 27

2-{3-[4-(4-Nitrophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (30 g), stannous chloride dihydrate (74.8 g) and ethanol(500 cc) are heated for one hour at 60° C. under a current of argon.Then sodium borohydride (1.3 g) is added over one hour in smallportions. Stirring is continued for one hour at 60° C., then for 15hours at a temperature of about 20° C. The mixture is poured into waterand ice (500 cc) then alkalinized with 4N caustic soda to pH 9. Theorganic phase is extracted with diethyl ether (4×200 cc), absorbed incharcoal 3S (3 g), dried on anhydrous magnesium sulphate, filtered andconcentrated to dryness under reduced pressure (200 mm Hg; 2.7 kPa). Theresidue obtained in purified by recrystallization, first from boiling1-propanol (250 cc), then twice from boiling ethanol (20 cc). 2-{3-[4-(4-Aminophenyl)-1-piperazinyl] propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (2.4 g) is thus obtained, m.p. 113° C.

EXAMPLE 28

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.4 g),triethylamine (4.2 cc) and 4-(3-fluorophenyl)piperazine (5.3 g) intoluene (100 cc). The mixture is heated for 8 hours at boiling point,then cooled to a temperature of about 20° C. After purification byflash-chromatography on a silica column, under a I current of argon atmedium pressure (0.5-1.5 bar) with dichloromethane and then a mixture ofdichloromethane and ethyl acetate (50-50 vol) as eluant, andrecrystallization from boiling acetonitrile (20 cc),2-{3-[4-(3-fluorophenyl)-1-piperazinyl]propyl)naphtho[1,8-cd]isothiazole1,1-dioxide (4.7 g) is obtained, m.p. 103° C.

4-(3-Fluorophenyl)piperazine may be prepared according to the methoddescribed by L. THUNUS et al., Ann. Pharm., 38, 353 (1980).

EXAMPLE 29

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7 g),triethylamine (3.5 cc) and 4-(2-fluorophenyl)piperazine (4.4 g) intoluene (150 cc). The mixture is heated for 8 hours at boiling point,then cooled to a temperature of about 20° C. After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with dichloromethane as eluant, andrecrystallization from boiling acetonitrile (15 cc),2-{3-[4-(2-fluorophenyl)-1-piperazinyl]propyl)naphtho[1,8-cd]isothiazole1,1dioxide (4.8 g) is obtained, m.p. 112° C.

4-(2-Fluorophenyl)piperazine may be prepared according to the methoddescribed by L. THUNUS et al., Ann. Pharm., 38, 353 (1980).

EXAMPLE 30

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7 g),triethylamine (3.5 cc) and 4-(4-methylphenyl)piperazine (4.4 g) intoluene (100 cc). The mixture is heated for 6 hours at boiling point,then cooled to a temperature of about 20° C. After purification,flash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with a mixture of dichloromethane andethyl acetate (80-20 vol) as eluant, and recrystallization from boilingacetonitrile (40 cc),2-{3-[4-(4-methylphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (4.5 g) is obtained, m.p. 136° C.

4-(4-Methylphenyl)piperazine may be prepared according to the methoddescribed by L. THUNUS et al., Ann. Pharm., 38, 353 (1980).

EXAMPLE 31

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7.2 g),triethylamine (3.6 cc) and 1-(4-piperidinyl)-2-benzimidazolinone (5.6 g)in dimethylformamide (100 cc). The mixture is heated for 8 hours atboiling point, then cooled to a temperature of about 20° C. Afterpurification by flash-chromatography on a silica column, under a currentof argon at medium pressure (0.5-1.5 bar) with a mixture ofdichloromethane and ethanol (95-5 vol) as eluant, and recrystallizationfrom boiling acetonitrile (200 cc),2-{3-[4-(2-oxo-1-benzimidazolinyl)piperidino]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.6 g) is obtained, m.p. 253° C.

1-(4-Piperidinyl)-2-benzimidazolinone may be prepared according to themethod described in U.S. Pat. No. 4,470,989.

EXAMPLE 32

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3.6 g),triethylamine (1.8 cc) and 4- (1,2-benzisoxazol-3-yl)piperazine (2.69)in dimethylformamide (200 cc). The mixture is heated for 8 hours atboiling point, then cooled to a temperature of about 20° C. Afterpurification by flash-chromatography on silica gel, under a current ofargon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant,and recrystallization from boiling acetonitrile (30 cc),2-{3-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.4 g) is obtained, m.p. 263° C.

4-(1,2-Benzisoxazol-3-yl)piperazine may be prepared according to themethod described by J. P. YEVICH et al., J. Med. Chem., 39, 359 (1986).

EXAMPLE 33

The experiment is carried out as in Example 1, starting with2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.3 g),triethylamine (3 cc) and 4-(1,2-benzisoxazol-3-yl)piperazine (4 g) andsodium iodide (3 g) in dimethylformamide (60 cc). The mixture is heatedfor 8 hours at boiling point, then cooled to a temperature of about 20°C. After purification by flash-chromatography on silica gel, under acurrent of argon at medium pressure (0.5-1.5 bar) with ethyl acetate aseluant, and recrystallization from boiling acetonitrile (22 cc),2-{2-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]ethyl}naphtho[1,8-cd]isothiazole1,1-dioxide (2.3 g) is obtained m.p. 148° C.

EXAMPLE 34

The experiment is carried out as in Example 1, startingwith2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.8 g),triethylamine (3 cc) and 4-(1,2-benzisoxazol-3-yl)piperazine (4 g) indimethylformamide (55 cc). The mixture is heated for 8 hours at boilingpoint, then cooled to a temperature of about 20° C. After purificationby flash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with ethyl acetate as eluant, andrecrystallization from boiling acetonitrile (15 cc),2-{4-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]butyl}naphtho[1,8-cd]isothiazole1,1-dioxide (2.2 g) is obtained, m.p. 138° C.

EXAMPLE 35

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (11 g),triethylamine (11 cc) and 4-(1,2-benzisothiazole-3-yl)piperazine (8.6 g)in dimethylformamide (120 cc). The mixture is heated for 8 hours atboiling point, then cooled to a temperature of about 20° C. Afterpurification by flash-chromatography on a silica column, under a currentof argon at medium pressure with ethyl acetate as eluant, andrecrystallization from boiling methyl ethyl ketone (160 cc),2-{3-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (4.4 g) is obtained, m.p. 172°-173° C.

EXAMPLE 36

The experiment is carried out as in Example 1, starting with2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.9 g),triethylamine (4.5 cc) and 4-(1,2-benzisothiazole-3-yl)piperazine (6.6g) in dimethylformamide (95 cc). The mixture is heated for 8 hours atboiling point, then cooled to a temperature of about 20° C. Afterpurification by flash-chromatography on a silica column, under a currentof argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant,and recrystallization from boiling acetonitrile (90 cc),2-{2-[4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl]ethyl}naphtho[1,8-cd]isothiazole1,1-dioxide (4.6 g) is obtained, m.p. 162°.

EXAMPLE 37

The experiment is carried out as in Example 1, startingwith2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.9 g),triethylamine (4.5 cc) and 4-(1,2-benzisothiazole-3-yl)piperazine (6.6g) in dimethylformamide (95 cc). The mixture is heated for 8 hours atboiling point, then cooled to a temperature of about 20° C. Afterpurification by flash-chromatography on a silica column, under a currentof argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant,and recrystallization from boiling acetonitrile (30 cc),2-{4-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl]butyl}naphtho[1,8-cd]isothiazole1,1-dioxide (6.3 g) is obtained, m.p. 123° C.

EXAMPLE 38

The experiment is carried out as in Example 1, startingwith2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.9 g),triethylamine (4.3 cc) and 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine(5.8 g) in toluene (80 cc). The mixture is heated for 8 hours at boilingpoint, then cooled to a temperature of about 20° C. Stirring ismaintained for 8 hours at this temperature. After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with ethyl acetate as eluant, andrecrystallization from boiling acetonitrile (25 cc),2-{4-[4-(4-chlorophenyl)1,2,3,6-tetrahydro-1-pyridyl]butyl}naphtho[1,8-cd]isothiazole1,1-dioxide (4.1 g) is obtained, m.p. 123° C.

EXAMPLE 39

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (11.2 g),triethylamine (16.8 cc) and 4- (3-hydroxyphenyl)piperazinedihydrobromide (13.6 g) in dimethylformamide (250 cc). The mixture isheated for 6 hours at boiling point, then cooled to a temperature ofabout 20° C. Stirring is maintained for 6 hours at this temperature.After purification by crystallization from isopropyl oxide (30 cc), thenrecrystallization from boiling acetonitrile (125 cc),2-{3-[4-(3-hydroxyphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (4.6 g) is obtained, m.p. 175° C.

4-(3-Hydroxyphenyl)piperazine dihydrobromide may be prepared in thefollowing manner the experiment is carried out as in Example 8 for thepreparation of 4-(4-hydroxyphenyl)piperazine dihydrobromide, startingwith 4-(3-methoxyphenyl)piperazine (25 g) and a 47% aqueous solution ofhydrobromic acid (360 cc). The mixture is heated at boiling point for 2hours, then cooled to a temperature of about 20° C. Stirring ismaintained for 15 hours at this temperature, then the mixture isconcentrated at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). Theresidual oil is redissolved in acetonitrile (100 cc); the precipitateformed is separated by filtration, washed with acetonitrile (2×50 cc)and isopropyl oxide (2×50 cc). 4-(3-Hydroxyphenyl)piperazinedihydrobromide (m.p.: 240° C.) (42.5 g) is obtained, which is used inthe crude state in the subsequent syntheses.

EXAMPLE 40

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7.02 g),triethylamine (10.5 cc) and 4-(2-hydroxyphenyl)piperazine dihydrobromide(8.5 g) in dimethylformamide (150 cc). The mixture is heated for 6 hoursat boiling point, then cooled to a temperature of about 20° C. Stirringis maintained for 15 hours at this temperature. After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with a mixture of dichloromethane andethyl acetate (50-50 vol) as eluant, and recrystallization fromacetonitrile (25 cc),2-{3-[4-(2-hydroxyphenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (5.8 g) is obtained, m.p. 128° C.

4-(2-Hydroxyphenyl)piperazine dihydrobromide may be prepared in thefollowing manner: the experiment is carried out as in Example 8 for thepreparation of 4-(4-hydroxyphenyl)piperazine dihydrobromide, startingwith 4-(2-methoxyphenyl)piperazine (25 g) and a 47% aqueous solution ofhydrobromic acid (360 cc). The mixture is heated at boiling point for 9hours, then cooled to a temperature close to 20° C. Stirring ismaintained for 15 hours at this temperature, then the mixture isconcentrated at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa) Theresidual oil is redissolved in acetonitrile (40 cc) and isopropyl oxide(40 cc); the precipitate formed is separated by filtration, washed withisopropyl oxide (2×50 cc). 4-(2-Hydroxyphenyl)piperazine dihydrobromide(m.p.: 235° C.) (18 g) is obtained, which is used in the crude state inthe subsequent syntheses.

EXAMPLE 41

The experiment is carried out as in Example 1, startingwith2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (10.68 g),triethylamine (5.6 cc), sodium iodide (6 g) and4-(3-indolyl)-1,2,3,6-tetrahydropyridine (8.0 g) in dimethylformamide(200 cc). The mixture is heated for 8 hours at boiling point, thencooled to a temperature of about 20° C. Stirring is continued for 2hours at this temperature. After purification by crystallization fromacetonitrile (150 cc) and recrystallization boiling methyl ethyl ketone(150 cc), 2-{2-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]ethyl}naphtho[1,8-cd]isothiazole1,1-dioxide (0.8 g) is obtained, m.p. 208° C.

EXAMPLE 42

The experiment is carried out as in Example 1, startingwith2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.95 g),sodium bicarbonate (0.84 g) and 4-(3-indolyl)-1,2,3,6-tetrahydropyridine(1.98 g) in a mixture of dimethylformamide (50 cc) and tetrahydrofuran(50 cc). The mixture is heated for 4 hours at boiling point, then cooledto a temperature of about 20° C. Stirring is maintained for 2 hours atthis temperature. After purification by crystallization from methylethyl ketone (15 cc) by flash-chromatography on a silica column, under acurrent of argon at medium pressure (0.5-1.5 bar) with dichloromethaneand then ethyl acetate as eluant, and recrystallization from boilingmethyl ethyl ketone (65 cc),2-{4-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]butyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.5 g) is obtained, m.p. 203° C.

EXAMPLE 43

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.81 g),triethylamine (1.4 cc) and 4-(4-chlorophenyl)piperidine (1.96 g) intoluene (30 cc). The mixture is heated for 8 hours at boiling point,then cooled to a temperature of about 20° C. Stirring is continued for 8hours at this temperature. After purification by flash-chromatography ona silica column, under a current of argon at medium pressure (0.5-1.5bar) with ethyl acetate as eluant, and recrystallization firstly fromboiling acetonitrile (12 cc) and then from boiling acetonitrile (17 cc),2-{3-[4-(4-chlorophenyl)piperidino]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.4 g) is obtained, m.p. 111° C.

4-(4-Chlorophenyl)piperidine may be prepared according to the methoddescribed by L. GOOTJES et al., Arzneim. Forsch., 17, 1145 (1967).

EXAMPLE 44

A mixture of2-{3-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (11 g) in dimethylformamide (150 cc) is added over 30minutes to sodium hydride (1.3 g) in a 50% dispersion in vaseline oil,under a current of argon, maintaining the temperature at about 20° C.The reaction medium is stirred for 2 hours at a temperature of about 20°C., then a solution of methyl iodide (3.9 g) in dioxane (50 cc) is addedover 15 minutes. Stirring is maintained for 15 hours at a temperature ofabout 20° C. The reaction mixture is redissolved in distilled water (250cc) and the organic phase is extracted with dichloromethane (4×100 cc)and then washed with distilled water (400 cc), dried over anhydrousmagnesium sulphate, filtered and concentrated to dryness at 40° C. underreduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purifiedby flash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with dichloromethane as eluant, andrecrystallized from boiling methyl ethyl ketone (70 cc).2-{3-[4-(1-Methyl-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (3.3 g) is obtained, m.p. 161° C.

EXAMPLE 45

The experiment is carried out as in Example 44, starting with2-{3-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (11 g) in dimethylformamide (150 cc), acetyl chloride (1.95cc) in dioxane (50 cc) and sodium hydride (1.3 g as a 50% dispersion invaseline oil). The mixture is stirred for 15 hours at a temperature ofabout 20° C. After purification by flash-chromatography on a silicacolumn, under a current of argon at medium pressure (0.5-1.5 bar),firstly with dichloromethane as eluant and then with ethyl acetate aseluant, then recrystallization from boiling acetonitrile (45 cc),2-{3-[4-(1-acetyl-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8cd]isothiazole1,1-dioxide (1.3 g) is obtained, m.p. 163° C.

EXAMPLE 46

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.8 g),4-hydroxy-4-(4-methylphenyl)piperidine (2.1 g) and sodium bicarbonate(0.94 g) in a mixture of dimethylformamide (60 cc) and tetrahydrofuran(50 cc). The mixture is heated for 5 hours at a temperature of about100° C. then cooled to a temperature of about 20° C. Stirring ismaintained for 15 hours at this temperature. After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with a mixture of dichloromethane andmethanol (95-5 vol) as eluant,2-{3-[4-(4-methylphenyl)-4-hydroxypiperidino]propyl}naphtho[1,8-cd]isophenythiazole 1,1-dioxide (1 g) is obtained, in the form of the hydrochlorideof m.p. 218° C.

4-Hydroxy-4-(4-methylphenyl)piperidine may be prepared in the followingmanner: 1-benzyl-4-hydroxy-4-(4-methylphenyl)piperidine (5 g), 5%palladium-on-charcoal (1 g) and methanol (100 cc) are charged into a 250cc bomb apparatus. The reaction medium is hydrogenated under pressure(52 bar) at 50° C. for 16 hours. After cooling to a temperature close to20° C. and purging with nitrogen, the mixture is filtered throughfritted glass and-washed with methanol (3×50 cc). The filtrate isconcentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7kPa). 4-Hydroxy-4-(4-methylphenyl)piperidine (3.4 g) is obtained in theform of a brown oil, which is used in the crude state in the subsequentsyntheses.

1-Benzyl-4-hydroxy-4-(4-methylphenyl)piperidine may be prepared in thefollowing manner: several drops of p-bromotoluene and a crystal ofiodine are added to magnesium turnings (1.7 g) in diethyl ether (25 cc),under a current of argon. The mixture in heated to boiling, then asolution of p-bromotoluene (12.1 g) in diethyl ether (70 cc) is pouredin in such a manner as to maintain the reflux. The reaction medium isstirred for 30 minutes at the boiling point of the solvent, then cooledto a temperature of about 20° C. A solution of 1-benzylpiperidone (6.7g) in diethyl ether (60 cc) is added, and stirring is maintained for 15hours at the same temperature. A saturated solution of ammonium chloride(150 cc) is added to the mixture; the aqueous phase is decanted and theorganic phase is extracted with diethyl ether (2×150 cc), dried overanhydrous magnesium sulphate, filtered and concentrated to dryness at40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtainedis purified by flash-chromatography on a silica column, under a currentof argon at medium pressure (0.5-1.5 bar) with a mixture ofdichloromethane and methanol (95-5 vol) as eluant. 1-Benzyl-4-hydroxy-4-((4-methylphenyl)piperidone (5 g) is obtained in the form of an oil,which is used in the crude state in the subsequent syntheses.

EXAMPLE 47

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.3 g),4-(3-indolyl)piperidine (4.5 g) and sodium bicarbonate (1.9 g) in amixture cf dimethylformamide (100 cc) and tetrahydrofuran (100 cc). Themixture is heated for 5 hours at boiling point, then cooled to atemperature of about 20° C. Stirring is maintained for 15 hours at thistemperature. After purification by flash-chromatography on a silicacolumn, under a current of argon at medium pressure (0.5-1.5 bar) withethyl acetate as eluant, and recrystallization from boiling methyl ethylketone (60 cc),2-{3-[4-(3-indolyl)piperidino]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (2 g) is obtained, m.p. 162° C.

4-(3-Indolyl)piperidine may be prepared according to the methoddescribed by J. BERGMAN et al., J. Het. Chem., 1071 (1970).

EXAMPLE 48

The experiment is carried out as in Example 1, starting with2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (1.2 g),4-(4-hydroxyphenyl)piparazine dihydrobromide (3.4 g) and sodiumbicarbonate (1.3 g) in dimethylformamide (30 cc). The mixture is heatedfor 4 hours at boiling point, then cooled to a temperature of about 20°C. After purification by flash-chromatography on a silica column, undera current of argon at medium pressure (0.5-1.5 bar) with ethyl acetateas eluant, and recrystallization from boiling acetonitrile (90 cc),2-{2-[4-(4-hydroxyphenyl)-1-piperazinyl]ethyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.6 g) is obtained, m.p. 235° C.

EXAMPLE 49

The experiment is carried out as in Example 1, starting with2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (3 g),4-(4-hydroxyphenyl)piperazine dihydrobromide (3.8 g) and sodiumbicarbonate (2.8 g) in a mixture of dimethylformamide (30 cc) andtetrahydrofuran (20 cc). The mixture is heated for 5 hours at boilingpoint, then cooled to a temperature of about 20° C. After purificationby recrystallization from boiling acetone (215 cc),2-{4-[4-(4-hydroxyphenyl)-1-piperazinyl]butyl}naphtho[1,8-cd]isothiazole1,1-dioxide (3.1 g) is obtained, m.p. 195° C.

EXAMPLE 50

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.1 g), sodiumbicarbonate (0.6 g) and4-(5-fluoro-3-indolyl)-1,2,3,6-tetrahydropyridine(1.6 g) indimethylformamide (15 cc) and tetrahydrofuran (15 cc). The mixture isheated for 5 hours at boiling point, then cooled to a temperature ofabout 20° C. Stirring is maintained for 7 hours at this temperature.After purification by crystallization from water (50 cc) thenrecrystallization from a boiling acetone-ethanol mixture (50-50 vol) (50cc),2-{3-[4-(5-fluoro-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.8 g) is obtained, m.p. 224° C.

4-(5-Fluoro-3-indolyl)1,2,3,6-tetrahydropyridine may be preparedaccording to the method described by L. NEDELEC et al., Eur. J. Med.Chem., 22, 33 (1987). It has m.p. 175° C.

EXAMPLE 51

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.4 g), sodiumbicarbonate (0.7 g) and4-(5-chloro-3-indolyl)-1,2,3,6-tetrahydropyridine (2 g) indimethylformamide (15 cc) and tetrahydrofuran (15 cc). The mixture isheated for 5 hours at boiling point, then cooled to a temperature ofabout 20° C. Stirring is maintained for 7 hours at this temperature.After purification by crystallization from water (50 cc), thenrecrystallization from boiling acetonitrile (50 cc),2-{3-[4-(5-chloro-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (2.1 g) is obtained, m.p. 189° C.

4-(5-Chloro-3-indolyl)-1,2,3,6-tetrahydropyridine may be preparedaccording to the method described by L. NEDELEC et al., Eur. J. Med.Chem., 22, 33 (1987). It has m.p. 220° C.

EXAMPLE 52

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (7 g), sodiumbicarbonate (4.2 g) and4-(5-hydroxy-3-indolyl)-1,2,3,6-tetrahydropyridine (5.3 g) indimethylformamide (50 cc) and tetrahydrofuran (50 cc). The mixture isheated for 5 hours at boiling point, then cooled to a temperature ofabout 20° C. Stirring is maintained for 7 hours at this temperature.After purification by crystallization from water (100 cc), thenrecrystallization from a boiling acetone-ethanol mixture (50-50 vol) (80cc),2-{3-[4.(5-hydroxy-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (5.1 g) is obtained, m.p. 214° C.

4-(5-Hydroxy-3-indolyl)-1,2,3,6-tetrahydropyridine may be preparedaccording to the method described by L. NEDELEC et al., Eur. J. Med.Chem., 22, 33 (1987). It has m.p. 185° C.

EXAMPLE 53

The experiment is carried out as in Example 44, starting with2-{3-[4-(2-oxo-1-benzimidazolinyl)piperidino]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (4.6 g) in dimethylformamide (20 cc) and benzoyl chloride(1.4 g) in tetrahydrofuran (20 cc) and sodium hydride (0.48 g) as a 50%dispersion in vaseline oil. The mixture is stirred for 15 hours at atemperature of about 20° C. After purification by flash-chromatographyon a silica column, under a current of argon at medium pressure (0.5-1.5bar) with a dichloromethanemethanol (90-10 vol) mixture as eluant, andthen recrystallization from a boiling acetone/ethanol (90-10 vol)mixture (60 cc),2-{3-[4-(3-benzoyl-2-oxo-1-benzimidazolinyl)piperidino]propyl}naphto[1,8-cd]isothiazole 1,1-dioxide (2.9 g) is obtained, m.p. 133° C.

EXAMPLE 54

The experiment is carried out as in Example 1, starting with2-(3-chloropropyl)naphtho[1,8cd]isothiazole 1,1-dioxide (2.8 g),4-hydroxy-4-(4-bromophenyl)piperidine (2.4 g) and sodium bicarbonate(0.94 g) in a mixture of dimethylformamide (80 cc) and tetrahydrofuran(50 cc). The mixture is heated for 5 hours to a temperature of about100° C. then cooled to a temperature of about 20° C. Stirring ismaintained for 15 hours at this temperature. After purification byflash-chromatography on a

silica column, under a current of argon (0.5-1.5 bar) with a mixture ofdichloromethane and methanol (95-5 vol) as eluant, and recrystallizationfrom boiling ethyl acetate (50 cc),2-{3-4-(4-bromopheny-4-hydroxypiperidino]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.5 g) is obtained in the form of hydrochloride, of m.p.110° C.

4-Hydroxy-4-(4-bromophenyl)piperidine may be prepared according to themethod described in U.S. Pat. No. 3,575,990.

EXAMPLE 55

A mixture of2-{3-[4-(4-bromophenyl)-4-hydroxypiperidino]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (3.7 g), 12N hydrochloric acid (25 cc) and acetic acid (50cc) is refluxed under stirring for 16 hours. The solution is thenconcentrated to dryness at 60° C. under reduced pressure (0.5 mm Hg;0.07 kPa). The crude reaction product is redissolved in water (25 cc)and neutralized with sodium bicarbonate to pH 7. Extraction of thisaqueous phase with dichloromethane (3×50 cc) then drying with magnesiumsulphate leads to a brown oil which is purified by flash-chromatographyon a silica column, under a current of argon (0.5-1.5 bar) with amixture of dichloromethane and methanol (98-2 vol) as eluant. Afterrecrystallization from boiling ethanol (30 cc)2-{3-[4-(4-bromophenyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.5 g) is obtained, m.p. 105° C.

EXAMPLE 56

2-(3-Bromo-2-hydroxypropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (26.8g), triethylamine (11 cc) and 4-(4-fluorophenyl)piperazine (14.1 g) intoluene (280 cc) are heated at boiling point for 8 hours. The mixture isthen cooled to a temperature of about 20° C. and stirring is maintainedfor 15 hours at this temperature. The precipitate formed is separated byfiltration and washed with toluene (2×50 cc). The filtrate is evaporatedto dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). Theresidue obtained is purified by chromatography on a silica column, withethyl acetate as eluant, and recrystallized from boiling acetonitrile(120 cc).2-{3-[4-(4-Fluorophenyl)-1-piperazinyl]-2-hydroxypropyl)naphtho[1,8-cd]isothiazole1,1-dioxide (16.2 g) is obtained, m.p. 130° C.

2-(3-Bromo-2-hydroxypropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide may beprepared in the following manner: a solution ofnaphtho[1,8-cd]isothiazole 1,1-dioxide (41 g) in dimethylformamide (1000cc) is added over 2 hours under a current of argon to a suspension ofsodium hydride (9.6 g) in a 50% dispersion in vaseline oil indimethylformamide (100 cc), maintaining the temperature between 20° and35° C. The reaction medium is stirred for 30 minutes at a temperature ofabout 20° C., then 1,3-dibromo-2-hydroxypropane (20.5 cc) indimethylformamide (500 cc) is added over 10 minutes. Stirring ismaintained for 15 hours at a temperature of about 20° C. The reactionmixture is concentrated to dryness at 70° C. under reduced pressure (0.5mm Hg; 0.07 kPa). The residue is purified by chromatography on a silicacolumn, under a current of argon with a mixture of dichloromethane andmethanol (95-5 vol) as eluant.2-(3-Bromo-2-hydroxypropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (62.1g) is obtained, in the form of a green oil which is used in the crudestate in the subsequent syntheses.

EXAMPLE 57

A solution of2-{3-[4-(4-fluorophenyl)-1-piperaziny]-2-hydroxypropyl}naphtho[1,8-cd]isothiazole1,1-dioxide (4.41 g) in dimethylformamide (50 cc) is poured over 30minutes into a mixture of sodium hydride (0.53 g) in a 50% dispersion invaseline oil, and dimethylformamide (10 cc), under a current of argon,maintaining the temperature between 20° and 30° C. The reaction mediumis stirred for 1 hour at temperature of about 20° C. and then methyliodide (0.7 cc) is added over 10 minutes. Stirring is maintained for 15hours at a temperature of about 20° C. The mixture is redissolved indistilled water (200 cc) and the organic phase is extracted withdichloromethane (4×100 cc), dried over anhydrous magnesium sulphate,filtered and concentrated to dryness at 40° C. under reduced pressure(20 mm Hg; 2.7 kPa). The residue is purified by flash-chromatography ona silica column, under a current of argon at medium pressure (0.5-1.5bar) with ethyl acetate as eluant, and recrystallized from boilingacetonitrile (10 cc).2-{3-[4-(4-Fluorophenyl)-1-piperazinyl]-2-methoxypropyl)naphtho[1,8-cd]isothiazole1,1-dioxide (2.1 g) is obtained, m.p. 128° C.

EXAMPLE 58

2-{2-Bromo-3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (4.2 g), triethylamine (1.1 cc) and dimethylamine (0.5 cc)in toluene (50 cc) are introduced into a 250 cc bomb apparatus cooled toa temperature of about 0° C. The mixture is stirred and heated for 8hours to a temperature close to 120° C., then cooled to a temperature ofabout 20° C. Stirring is continued for 15 hours at this temperature,then the reaction mixture is concentrated to dryness at 40° C. underreduced pressure (20 mm Hg; 2.7 kPa). The residual oil is purified byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with ethyl acetate as eluant. Afterrecrystallization from boiling acetonitrile (15 cc),2-{2-dimethylamino-3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.9 g) is obtained, m.p. 118° C.

2-{2-Bromo-3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide may be prepared in the following manner: phosphorustribromide (1 cc) is poured into2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxypropyl)naphtho[1,8-cd]isothiazole1,1-dioxide (11.5 g) in toluene (150 cc). The mixture is heated atboiling point for 4 hours, then is cooled to a temperature of about 20°C. The reaction mixture is redissolved in distilled water (30 cc) andalkalinized to pH 11 with N caustic soda (20 cc). The organic phase isextracted with dichloromethane (4×300 cc), dried over anhydrousmagnesium sulphate, filtered and concentrated to dryness at 40° C. underreduced pressure (20 mm Hg; 2.7 kPa). The residual oil is purified byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with ethyl acetate as diluent.2-{2-Bromo-3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole1,1-dioxide (5.7 g) is obtained, m.p. 102° C., which is used in thecrude state in the subsequent syntheses.

EXAMPLE 59

The experiment is carried out as in Example 56, starting with2-(3-chloro-2-methylpropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (10.4g), triethylamine (5.1 cc), sodium iodide (5.4 g) and4-(4-fluorophenyl)piperazine (6.5 g) in toluene (130 cc). The mixture isheated at boiling point for 16 hours, then cooled to a temperature ofabout 20° C. After purification by flash chromatography on a silicacolumn, under a current of argon at medium pressure (0.5-1.5 bar) withdichloromethane and then ethyl acetate as eluants, and recrystallizationfrom boiling acetonitrile (20 cc),2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-methylpropyl}naptho[1,8-cd]isothiazole1,1-dioxide (3.1 g) is obtained m.p. 133° C.

2-(3- Chloro-2-methylpropyl)naphthol1,8-cd]isothiazole 1,1-dioxide maybe prepared in the following manner: the experiment is carried out as inExample 56 for the preparation of2-(3-bromo-2-hydroxypropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide,starting with naphtho[1,8-cd]isothiazole 1,1-dioxide (10.3 g) indimethylformamide (125 cc), sodium hydride (2.4 g) in a 50% dispersionin vaseline oil, and 1-bromo-3-chloro-2-methylpropane (5.9 cc). Afterpurification by flash-chromatography on a silica column, under a currentof argon at medium pressure (0.5-1.5 bar) with a mixture ofdichloromethane and cyclohexane (80-20 vol) as eluant,2-(3-chloro-2-methylpropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (10.4g) is obtained, in the form of a green oil, which is used in the crudestate in the subsequent syntheses.

EXAMPLE 6

A solution of naphtho[1,8-cd]isothiazole 1,1-dioxide (3.25 g) indimethylformamide (50 cc) is poured over 30 minutes into a mixture ofsodium hydride (0.76 g) in a 50% dispersion in vaseline oil anddimethylformamide (10 cc), under a current of argon. The reaction mediumis stirred for 2 hours at a temperature of about 20° C.1-(4-bromo-2-butyl)-4-(4-fluorophenyl)piperazine (5 g) indimethylformamide (100 cc) is added over 10 minutes. The reactionmixture is stirred for 15 hours at a temperature close to 20° C., thenconcentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7kPa). The residual oil is purified by flash-chromatography on silicacolumn, under a current of argon at medium pressure (0.5-1.5 bar) with amixture of dichloromethane and ethyl acetate (80-20 vol) as eluant.After recrystallization from boiling acetonitrile (13 cc),2-{3-[4-(4-fluorophenyl)-1-piperazinyl]butyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.8 g) is obtained, m.p. 122° C.

1-(4-Bromo-2-butyl)-4-(4-fluorophenyl)piperazine may be prepared in thefollowing manner: phosphorus tribromide (1.6 cc) is poured into asolution of 1-(4-hydroxy-2-butyl)-4-(4-fluorophenyl)piperazine (12.7 g)in toluene (200 cc). The mixture is heated for 1 hour at a temperatureof about 60° C., then is cooled to a temperature close to 20° C. Thereaction mixture is redissolved in distilled water (200 cc) andalkalinized to pH 11 with N caustic soda (30 cc). The organic phase isextracted with dichloromethane (2×100 cc), dried over anhydrousmagnesium sulphate, filtered and concentrated to dryness at 40° C. underreduced pressure (20 mm Hg; 2.7 kPa). The residual oil is purified byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with a mixture of ethyl acetate andmethanol (50-50 vol) as eluant. 1-(4-Bromo-2-butyl)-4-(4-fluorophenyl)piperazine (5 g) is obtained, in the form of a pale yellow oil, which isused in the crude state in the subsequent syntheses.

1-(4-Hydroxy-2-butyl)-4-(4-fluorophenyl)piperazine may be prepared inthe following manner; 3-bromo-butanol (29 g), triethylamine (26.6 cc)and 4-(4-fluorophenyl) piperazine (34 g) in toluene (800 cc) are heatedat boiling point for 8 hours. The mixture is then cooled to atemperature of about 20° C. and stirring is maintained for 15 hours atthis temperature. The precipitate formed is separated by filtration andwashed with toluene (2×50 cc). The filtrate is redissolved in distilledwater (400 cc), the organic phase is decanted, dried over anhydrousmagnesium sulphate and concentrated to dryness at 40° C. under reducedpressure (20 mm Hg; 2.7 kPa). The residual oil is purified byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with ethyl acetate and then a mixture ofethyl acetate and methanol (95-5 vol) as eluant.1-(4-Hydroxy-2-butyl)-4-(4-fluorophenyl)piperazine(l2.7 g)is obtained,in the form of a yellow oil, which is used in the crude state in thesubsequent syntheses.

3-Bromobutanol may be prepared according to the method described by D.A. PALAVANDISHVILI et al., Chem. abstr., 70, 106089.

EXAMPLE 61

The experiment is carried out as in Example 56, starting with2-(4-bromo-2-butyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.2 g),triethylamine (2.1 cc) and 4-(4-fluorophenyl)piperazine (2.8 g) intoluene (200 cc). The mixture is heated at boiling point for 8 hours andthen cooled to a temperature of about 20° C. After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with a mixture of dichloromethane andethyl acetate (90-10 vol) as eluant, crystallization from isopropyloxide (30 cc) and recrystallization from boiling acetonitrile (10 cc),2-{4-[4-(4-fluorophenyl)-1-piperazinyl]-2-butyl}naphtho[1,8-cd]isothiazole1,1-dioxide (1.2 g) is obtained, m.p. 116° C.

2-(4-Bromo-2-butyl)naphtho[1,8-cd]isothiazole 1,1-dioxide may beprepared in the following manner: phosphorus tribromide (1.8 cc) ispoured into a solution of2-(4-hydroxy-2-butyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (16.1 g) intoluene (250 cc). The mixture is heated for 2 hours at a temperature ofabout 60° C. then cooled to a temperature close to 20° C. The reactionmixture is redissolved in distilled water (200 cc), the organic phase isextracted with toluene (3×50 cc), dried over anhydrous magnesiumsulphate, filtered and concentrated to dryness at 40° C. under reducedpressure (20 mm Hg; 2.7 kPa).2-(4-Bromo-2-butyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.2 g) isobtained, in the form of a brown oil, which is used in the crude statein the subsequent syntheses.

2-(4-Hydroxy-2-butyl)naphtho[1,8-cd]-isothiazole 1,1-dioxide may beprepared in the following manner: the experiment is carried out inExample 56 for the preparationof2-(3-bromo-2-hydroxy-1-propyl)naphtho[1,8-cd]isothiazole 1,1-dioxide,starting with naphtho[1,8-cd]isothiazole 1,1-dioxide (49.6 g) indimethylformamide (350 cc), sodium hydride (11.6 g) in a 50% dispersionin vaseline oil, and 2-bromobutanol (37.1 g). After purification byflash-chromatography on a silica column, under a current of argon atmedium pressure (0.5-1.5 bar) with a mixture of dichloromethane andethyl acetate (50-50 vol) as eluant,2-(4-hydroxy-2-butyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (16.1 g) isobtained, in the form of a brown oil, which is used in the crude statein the subsequent syntheses.

The pharmaceutical compositions of the invention are constituted by acompound of formula (I) in the free form or in the form of an additionsalt with a pharmaceutically acceptable acid, in the pure state or inthe form of a composition in which it is associated with any otherpharmaceutically compatible product, which may be inert, e.g. a carrieror coating, or physiologically active. The medicaments according to theinvention may be used orally, parenterally, rectally or topically.

Tablets, pills, powders (gelatine capsules, sachets) or granules may beused as solid compositions for oral administration. In thesecompositions, the active principle according to the invention is mixedwith one or more inert diluents, such as starch, cellulose, sucrose,lactose or silica, under a current of argon. These compositions may alsocontain substances other than diluents, for example one or morelubricants such as magnesium stearate or talc, a colorant, a coating(sugar-coated pills) or a varnish.

Pharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs containing inert diluents such as water, ethanol, glycerol,vegetable oils or paraffin oil may be used as liquid compositions fororal administration. These compositions may contain substances otherthan diluents, for example wetting, sweetening, thickening, flavoring orstabilizing products.

Sterile compositions for parenteral administration may preferably beaqueous or non-aqueous solutions, suspensions or emulsions. Water,propylene glycol, polyethylene glycol, vegetable oils, in particularolive oil, injectable organic esters, for example ethyl oleate, or othersuitable organic solvents may be used as solvent or vehicle. Thesecompositions may also contain adjuvants, in particular wetting,isotonifying, emulsifying, dispersing and stabilizing agents.Sterilization may be carried out in several ways, for example by asepticfiltration, by incorporating sterilizing agents into the composition, byirradiation or by heating. The sterile compositions may also be preparedin the form of sterile solid compositions which can be dissolved at themoment of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectalcapsules which contain, in addition to the active product, excipientssuch as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical administration may be for creams,ointments, lotions, collyria, collutories, nasal drops or aerosols.

In human therapeutics, the compounds according to the invention areparticularly useful for the treatment of ailments in which serotonin isinvolved, and in particular ailments of the central nervous system, thecardiovascular system and intestinal disorders. They are particularlyuseful for the treatment of anxiety, sleeping disorders, depression,psychoses and in particular schizophrenia, migraine, asthma,hypertension and urticaria, as analgesics and as inhibitors of plateletaggregation.

Doses depend on the required effect, on the length of treatment and onthe administration route used; they are generally between 10 and 300 mgper day by the oral route for an adult, with single doses ranging from 2to 10 mg of active substance.

The doctor will generally determine the appropriate posology as afunction of the age, the weight and all other factors of the subject tobe treated.

The following examples illustrate some compositions according to theinvention:

EXAMPLE A

Soft capsules containing 50 mg of active product are prepared, accordingto the normal technique, with the following composition:

    ______________________________________                                        2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-                                                               50 mg                                                2-hydroxypropyl}naphtho[1,8-cd]isothiazole                                    1,1-dioxide                                                                   cellulose                18 mg                                                lactose                  55 mg                                                colloidal silica, under a current of argon                                                              1 mg                                                sodium carboxymethylstarch                                                                             10 mg                                                talc                     10 mg                                                magnesium stearate        1 mg                                                ______________________________________                                    

EXAMPLE B

Tablets containing 50 mg of active product are prepared, according tothe normal technique, with the following composition:

    ______________________________________                                        2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-                                                              50 mg                                                 2-methoxypropyl}naphtho[1,8-cd]isothiazole                                    1,1-dioxide                                                                   lactose                 104 mg                                                cellulose               40 mg                                                 polyvidone              10 mg                                                 sodium carboxymethylstarch                                                                            22 mg                                                 talc                    10 mg                                                 magnesium stearate       2 mg                                                 colloidal silica, under a current of argon                                                             2 mg                                                 mixture of hydroxymethylcellulose, glycerine                                                          quantity sufficient                                   and titanium oxide (72-3.5-24.5)                                                                      for 1 tablet                                                                  coated to finish at                                                           245 mg                                                ______________________________________                                    

EXAMPLE C

An injectable solution containing 10 mg of active product is preparedwith the following composition:

    ______________________________________                                        2-{2-dimethylamino-3-[4-(4-fluoro-                                                               10         mg                                              phenyl)-1-piperazinyl]propyl}                                                 naphtho[1,8-cd] isothiazole                                                   1,1-dioxide                                                                   benzoic acid       80         mg                                              benzyl alcohol     0.06       cc                                              sodium benzoate    80         mg                                              95% ethanol        0.4        cc                                              sodium hydroxide   24         mg                                              propylene glycol   1.6        cc                                              water              quantity sufficient to produce                                              4        cc                                                  ______________________________________                                    

Although the invention has been described in conjunction with specificembodiments, it is evident that many alternatives and variations will beapparent to those skilled in the art in light of the foregoingdescription. Accordingly, the invention is intended to embrace all ofthe alternatives and variations that fall within the spirit and scope ofthe appended claims. The above references are hereby incorporated byreference.

We claim:
 1. A compound of formula: ##STR11## in which R₁ representsa1,2,3,6-tetrahydro-1-pyridyl radical substituted in the 4-position by(a) a phenyl radical, (b) a phenyl radical substituted by a halogen atomor an alkyl, hydroxy or alkoxy radical, (c) a 3-indolyl radical, (d) a3-indolyl radical substituted on the nitrogen atom by an alkyl oralkylcarbonyl radical and/or in the 5-position by a chlorine or fluorineatom or (e) a 3-(5-hydroxyindolyl) radical, a 1-piperazinyl radicalsubstituted in the 4-position by (a) a phenyl radical, (b) a phenylradical substituted by an alkoxy, alkyl, hydroxy, nitro or amino radicalor a halogen atom, (c) a 1,2-benzisothiazol-3-yl radical, (d) a1,2-benzisoxazol-3-yl radical or (e) a 2-pyridyl radical, a piperidinoradical substituted in the 4-position by (a phenyl radical, (b) a phenylradical substituted by a halogen atom or a hydroxy, alkyl or alkoxyradical, (c) two phenyl radicals, (d) a bis(4-fluorophenyl)methyleneradical, (e) a 4-fluorobenzoyl radical, (f) a 2-oxo-1-benzimidazolinylradical, (g) a 2-oxo-1-benzimidazolinyl radical substituted in the3-position by an alkylcarbonyl or benzoyl radical, (h) a hydroxy radicaland a phenyl radical optionally substituted by an alkyl, alkoxy orhydroxy radical or a halogen atom, (i) a 3-indolyl radical, (j) a3-indolyl radical substituted on the nitrogen atom by an alkyl oralkylcarbonyl radical and/or in the 5-position by a chlorine or fluorineatom or (k) a 3-(5-hydroxyindolyl) radical, R₂, R₃ and R₄ represent ahydrogen atom and R₅ represents a nitrogen atom, R₆ represents analkylene chain containing 2 to 4 carbon atoms or a propylene chainsubstituted in the 1- or 3-position by an alkyl radical or in the2-position by an alkyl, alkoxy, hydroxy, dialkylamino, piperidino,morpholino or thiomorpholino radical,with the reservation that when R₆represents a propylene radical substituted int he 2-position by adialkylamino, piperidino, morpholino or thiomorpholino radical, R₁cannot be a radical containing a hydroxy radical and it being understoodthat the alkyl and alkoxy radicals and the alkyl and alkoxy portionscontain 1 to 4 carbon atoms in a straight or branched chain, and itssalts with inorganic or organic acids.
 2. A compound according to claim1 in which the halogen atoms are chlorine or bromine atoms.
 3. Acompound according to claim 1 in which R₁ represents a1,2,3,6-tetrahydro-1-pyridyl radical substituted in the 4-position by ahalophenyl radical, a phenyl radical or a 3-indolyl radical substitutedon the nitrogen atom by alkyl or alkylcarbon radical, a 1-piperazinylradical substituted in the 4-position by a-2-pyridyl radical,1,2-benzisothiazol-3-yl radical or phenyl radical substituted by ahalogen atom or a hydroxy, amino or alkyl radical or a piperidinoradical substituted in the 4-position by a phenyl or N-alkyl-3-indolylradical.
 4. A pharmaceutical composition useful for the treatment ofailments in which serotonin is implicated comprising an effective amountof at least one compound according to claim 1 in the free form or in theform of an addition salt with a compatible, pharmaceutically acceptablecarrier or coating.
 5. A method for the treatment of ailments in whichserotonin is implicated which comprises administering to a subject inneed of such treatment, an effective amount of a compound according toclaim 1 in the free form or in the form of an addition salt withpharmaceutically acceptable salt.